Derivatives of heterocycles with 5 members, their preparation and their use as medicaments

ABSTRACT

A method of treating Parkinson&#39;s disease in warm-blooded animals comprising administering to warm-blooded animals in need thereof an amount of a compound of the formula  
                 
in racemic, enantiomeric form or any combination of these forms, wherein the substituents are as defined in the specification.

The present invention relates to the use of compounds of general formula(I) for preparing a medicament intended to inhibit monoamine oxydases(MAO) and/or lipidic peroxidation and/or to act as modulators of thesodium channels. A subject of the invention is also, as medicaments, thecompounds of general formula (II) defined hereafter. Moreover it relatesto new compounds of general formula (III).

The compounds mentioned above often present 2 or 3 of the activitiesmentioned above, which confer advantageous pharmacological properties onthem.

In fact, taking into account the potentiel role of the MAO's and ROS's(“reactive oxygen species”, at the origin of lipidic peroxidation) inphysiopathology, the new described derivatives corresponding to generalformula (I) can produce beneficial or favorable effects in the treatmentof pathologies where these enzymes and/or these radicular species areinvolved. In particular:

-   -   disorders of the central or peripheral nervous system such as        for example neurological diseases where Parkinson's disease,        cerebral or spinal cord traumatisms, cerebral infarction, sub        arachnoid hemorrhage, epilepsy, ageing, senile dementia,        Alzheimer's disease, Huntington's chorea, amyotrophic lateral        sclerosis, peripheral neuropathies, pain can in particular be        mentioned;    -   schizophrenia, depressions, psychoses;    -   disorders of the memory and the humour;    -   pathologies such as for example migraine;    -   behavioural disorders, bulimia and anorexia;    -   auto-immune and viral diseases such as for example lupus, AIDS,        parasitic and viral infections, diabetes and its complications,        multiple sclerosis.    -   addiction to toxic substances;    -   proliferative and inflammatory pathologies;    -   and more generally all the pathologies characterised by an        excessive production of ROS's and/or participation of MAO's.

In all of these pathologies, experimental evidence exists whichdemonstrates the involvement of ROS's (Free Radic. Biol. Med. (1996) 20,675-705; Antioxid. Health. Dis. (1997) 4 (Handbook of SyntheticAntioxidants), 1-52) as well as the involvement of MAO's (Goodman &Gilman's: The pharmacological basis of therapeutics, 9th ed., 1995,431-519).

The advantage of a combination of the inhibitory activities of MAO andinhibition of lipidic peroxidation is for example well illustrated inParkinson's disease. This pathology is characterized by a loss ofdopaminergic neurons of the nigrostriatal route the cause of which wouldin part be linked to an oxidizing stress due to ROS's. The exogenicdopamine from L Dopa is used in therapeutics in order to maintainsufficient levels of dopamine. MAO inhibitors are also used with L Dopato avoid its metabolic degradation but do not act on the ROS's.Compounds which act both on MAO's and ROS's will therefore have acertain advantage.

Moreover, the character of the modulator of the sodium channels is veryuseful for therapeutic indications such as:

-   -   the treatment or prevention of pain, and in particular:        -   post-operative pain,        -   migraine,        -   neuropathic pain such as trigeminal neuralgia, post-herpetic            pain, diabetic neuropathies, glossopharyngeal neuralgias,            secondary radiculopathies and neuropathies associated with            metastatic infiltrations, adiposis dolorosa and pain            associated with burns,        -   central pain as a result of vascular cerebral accidents,            thalamic lesions and multiple sclerosis, and        -   chronic inflammatory pain or pain linked to a cancer;    -   the treatment of epilepsy;    -   the treatment of disorders linked to neurodegeneration, and in        particular:        -   vascular cerebral accidents,        -   cerebral traumatism, and        -   neurodegenerative diseases such as Alzheimer's disease,            Parkinson's disease and amyotrophic lateral sclerosis;    -   the treatment of bipolar disorders and irritable colon syndrome.

The concrete advantages of the presence in a compound of at least one ofthese activities is therefore clearly apparent from the above.

The European Patent Application EP 432 740 describes derivatives ofhydroxyphenylthiazoles, which can be used in the treatment ofinflammatory diseases, in particular rheumatic diseases. Thesederivatives of hydroxyphenylthiazoles show properties of trapping freeradicals and inhibitors of the metabolism of arachidonic acid (theyinhibit lipoxygenase and cyclooxygenase).

Other derivatives of hydroxyphenylthiazoles or hydroxyphenyloxazoles aredescribed in the PCT Patent Application WO 99/09829. These haveanalgesic properties.

A certain number of derivatives of imidazoles with close or identicalstructures to those of the compounds corresponding to general formula(I) according to the invention have moreover been described by theApplicant in the PCT Patent Application WO 99/64401 as agonists orantagonists of somatostatin. However, said derivatives of imidazoleshave therapeutic properties in fields different from those indicatedabove (suppression of the growth hormone and the treatment ofacromegalia, treatment of the recurrence of stenosis, inhibition of thesecretion of gastric acid and prevention of gastro-intestinal bleedingin particular).

Moreover, the compounds of general formula (A1)

in whichR1 represents one of the aryl, heteroaryl, aralkyl or cycloalkylradicals optionally substituted by one to three substituents chosenindependently from a halogen atom, the CF₃, CN, OH, alkyl or alkoxyradical, SO₂R9 with R9 representing NH₂ or NHCH₃,X represents NR2, R2 representing H or alkyl;Y represents N or CR3;Z represents CR3 or N;on the condition however that Y and Z are not both CR3 or N at the sametime;R3 represents H, alkyl, halogen, hydroxyalkyl or phenyl optionallysubstituted by 1 to 3 substituents chosen from H, CF₃, CN, SO₂NH₂, OH,alkyl or alkoxy;m represents 0, 1 or 2;R4 represents H or alkyl;when Z represents CR3, then R3 and R4 can also represent together—(CH₂)_(n1)— with n1 an integer from 2 to 4 or R2 and R4 can alsorepresent together —(CH₂)_(n2)— with n2 an integer from 2 to 4;R5 and R6 represent independently H, alkyl, alkoxy, aryl or aralkyl;NR5R6 can also represent together (in particular):

-   -   the optionally substituted        2-(1,9,3,4-tetrahydroquinolyl)radical,    -   a        radical in which R7 represents one of the phenyl, benzyl or        phenethyl radicals in which the phenyl ring can be substituted;    -   a        radical in which p is an integer from 1 to 3,        W is N and R8 represents H, CF₃, one of the phenyl, pyridyl or        pyrimidinyl radicals optionally substituted once to twice by        radicals chosen from halogen, OH, alkyl or alkoxy, or        W is CH and R8 represents phenyl optionally substituted or        aralkyl optionally substituted on the aryl group;        have been described in the PCT Patent Application WO 96/16040 as        partial agonists or antagonists of the dopamine sub-receptors of        the brain or as prodrug forms of such partial agonists or        antagonists. Therefore these compounds would have useful        properties in the diagnosis and treatment of affective disorders        such as schizophrenia and depression as well as certain        disorders of movement such as Parkinson's disease.

It has also been described in the PCT Patent Application WO 98/27108that certain amides of general formula (A2)

in which:R1 represents in particular an alkyl, optionally substituted phenyl oroptionally substituted heterocyclic aryl radical;R2 represents H or phenylalkyl;R4 represents H, quinolyl, 3-4-methylenedioxyphenyl or one of the phenylor pyridyl radicals optionally substituted, by a radical or radicalschosen in particular from alkyl, alkoxy, alkylthio, optionally protectedhydroxy, amino, alkylamino, dialkylamino;R5 represents H or an imidazolyl, phenyl, nitrophenyl, phenylalkylradical, or also a —CO—N(R7)(R8) radical, in which R7 and R8 representindependently H, phenyl, phenylalkyl, alkyl or alkoxy;or R4 and R5 in combination form a group of formula —CH═CH—CH═CH—;Y is a phenylene radical substituted by a phenyl, phenoxy orphenylalkoxy radical, or a group of formula —CH(R3)-, in which R3represents H or a radical of formula —(CH₂)_(n)—R6, in which R6represents an optionally protected hydroxy, acyl, carboxy, acylamino,alkoxy, phenylalkoxy, alkylthio, optionally substituted phenyl,optionally substituted pyridyl, pyrazinyl, pyrimidinyl, furyl,imidazolyl, naphthyl, N-alkylindolyl or 3,4-methylenedioxyphenyl radicaland n is an integer from 0 to 3;R2 and R3 taken together with the carbon atoms which carry them can forma phenyl group;X represents S or NR9;R9 representing H, an alkyl or cycloalkyl radical, or also a benzylradical optionally substituted once on its phenyl part by H, alkyl oralkoxy;are inhibitors of the NO synthases and can be used to treat diseaseswhich include in particular cardiovascular or cerebral ischemia,cerebral hemorrhage, disorders of the central nervous system,Alzheimer's disease, multiple sclerosis, diabetes, hepatitis, migraine,rheumatoid arthritis and osteoporosis.

In a different field, the Applicant has itself previously described inthe PCT Patent Application WO 98/58934 derivatives of amidines havingthe ability to inhibit NO synthases and/or lipidic peroxidation.

The Applicant has now unexpectedly discovered that certain intermediatesof the first stages of synthesis of the amidines described in the PCTPatent Application WO 98/58934, and more generally certain derivativesof heterocycles with five members, namely the products of generalformula (I) defined hereafter, have at least one of the three propertieschosen from the following properties (and often even two of these threeproperties even sometimes all three at the same time):

-   -   MAO inhibition properties;    -   lipidic peroxidation inhibition properties; and    -   properties of modulating the sodium channels.

These advantageous properties offer the advantage of opening up numeroususes for such compounds, in particular in the treatment ofneurodegenerative diseases, and in particular those indicatedpreviously, of pain or of epilepsy.

According to the invention, the compounds corresponding to generalformula (I)

in racemic, enantiomeric form or any combination of these forms, inwhich Het is a heterocycle with 5 members comprising 2 heteroatoms andsuch that general formula (I) corresponds exclusively to one of thefollowing sub-formulae:

in whichA representseither a

radical in which R³ represents a hydrogen atom, the OH group or analkoxy or alkyl radical,or a

radical in which R⁴, R⁵, R⁶, R⁷ and R⁸ represent, independently, ahydrogen atom, a halogen, the OH group or an alkyl, alkoxy, cyano, nitroor NR¹⁰R¹¹ radical, R¹⁰ and R¹¹ representing, independently, a hydrogenatom, an alkyl radical or a —COR¹² group, or R¹⁰ and R¹¹ formingtogether with the nitrogen atom an optionally substituted heterocyclecontaining 4 to 7 members and 1 to 3 heteroatoms including the nitrogenatom already present, the additional heteroatoms being chosenindependently from the group constituted by the O, N and S atoms, saidheterocycle being able to be for example azetidine, pyrrolidine,piperidine, piperazine, morpholine or thiomorpholine, R¹² representing ahydrogen atom or an alkyl, alkoxy or NR¹³R¹⁴ radical, R¹³ and R¹⁴representing, independently, a hydrogen atom or an alkyl radical, or R¹³and R¹⁴ forming together with the nitrogen atom an optionallysubstituted heterocycle containing 4 to 7 members and 1 to 3 heteroatomsincluding the nitrogen atom already present, the additional heteroatomsbeing chosen independently from the group constituted by the O, N and Satoms, said heterocycle being able to be for example azetidine,pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, R⁹represents a hydrogen atom, an alkyl radical or a —COR¹⁵ group,R¹⁵ representing a hydrogen atom or an alkyl, alkoxy or NR¹⁶R¹⁷ radical,R¹⁶ and R¹⁷ representing, independently, a hydrogen atom or an alkylradical, or R¹⁶ and R¹⁷ forming together with the nitrogen atom anoptionally substituted heterocycle containing 4 to 7 members and 1 to 3heteroatoms including the nitrogen atom already present, the additionalheteroatoms being chosen independently from the group constituted by theO, N and S atoms, said heterocycle being able to be for exampleazetidine, pyrrolidine, piperidine, piperazine, morpholine orthiomorpholine, and W doesn't exist, or represents a bond, or —O—, —S—or —NR¹⁸—, in which R¹⁸ represents a hydrogen atom or an alkyl radical;either a

radical in which Q represents H, —OR²², —SR²²—, —NR²³R²⁴, a phenylradical optionally substituted by one or more substituents chosenindependently from a halogen atom, an OH, cyano, nitro, alkyl, alkoxy or—NR¹⁰R¹¹ radical and a group with two substituents representing togethera methylenedioxy or ethylenedioxy radical, or also Q represents a —COPh,—SO₂Ph or —CH₂Ph radical, said —COPh, —SO₂Ph or —CH₂Ph radical beingoptionally substituted on its aromatic part by one or more of thesubstituents chosen independently from an alkyl or alkoxy radical and ahalogen atom,R¹⁰ and R¹¹ representing, independently, a hydrogen atom, an alkylradical or a —COR¹² group, or R¹⁰ and R¹¹ forming together with thenitrogen atom an optionally substituted heterocycle containing 4 to 7members and 1 to 3 heteroatoms including the nitrogen atom alreadypresent, the additional heteroatoms being chosen independently from thegroup constituted by the O, N and S atoms, said heterocycle being ableto be for example azetidine, pyrrolidine, piperidine, piperazine,morpholine or thiomorpholine, R¹² representing a hydrogen atom, an alkylor alkoxy or NR¹³R¹⁴ radical,R¹³ and R¹⁴ representing, independently, a hydrogen atom or an alkylradical, or R¹³ and R¹⁴ forming together with the nitrogen atom anoptionally substituted heterocycle containing 4 to 7 members and 1 to 3heteroatoms including the nitrogen atom already present, the additionalheteroatoms being chosen independently from the group constituted by theO, N and S atoms, said heterocycle being able to be for exampleazetidine, pyrrolidine, piperidine, piperazine, morpholine orthiomorpholine,R²² representing a hydrogen atom, an alkyl radical or an aryl radicaloptionally substituted by one or more substituents chosen from thealkyl, OH, halogen, nitro and alkoxy radicals,R²³ and R²⁴ representing, independently, a hydrogen atom, an alkylradical or a —CO—R²⁵ radical,R²⁵ representing an alkyl radical,and R¹⁹, R²⁰ and R²¹ represent, independently, a hydrogen, a halogen,the OH or SR²⁶ group, or an alkyl, cycloalkyl, alkenyl, alkoxy, cyano,nitro, —SO₂NHR⁴⁹, —CONHR¹⁵, —S(O)_(q)R⁵⁶, —NH(CO)R⁵⁷, —CF₃, —OCF₃ orNR²⁷R²⁸ radical,R²⁶ representing a hydrogen atom or an alkyl radical,R²⁷ and R²⁸ representing, independently, a hydrogen atom, an alkylradical or a —COR²⁹ group, or R²⁷ and R²⁸ forming together with thenitrogen atom an optionally substituted heterocycle containing 4 to 7members and 1 to 3 heteroatoms including the nitrogen atom alreadypresent, the additional heteroatoms being chosen independently from thegroup constituted by the O, N and S atoms, said heterocycle being ableto be for example azetidine, pyrrolidine, piperidine, piperazine,morpholine or thiomorpholine,R⁴⁹ and R⁵⁵ representing, independently each time that they occur, ahydrogen atom or an alkyl or alkylcarbonyl radical,q representing an integer from 0 to 2,R⁵⁶ and R⁵⁷ representing, independently each time that they occur, ahydrogen atom or an alkyl or alkoxy radical,R²⁹ representing a hydrogen atom, an alkyl, alkoxy or —NR³⁰R³¹ radical,R³⁰ and R³¹ representing, independently, a hydrogen atom or an alkylradical, or R³⁰ and R³¹ forming together with the nitrogen atom anoptionally substituted heterocycle containing 4 to 7 members and 1 to 3heteroatoms including the nitrogen atom already present, the additionalheteroatoms being chosen independently from the group constituted by theO, N and S atoms, said heterocycle being able to be for exampleazetidine, pyrrolidine, piperidine, piperazine, morpholine orthiomorpholine,or a

radical in which R³² represents a hydrogen atom or an alkyl radical, andT represents a —(CH₂)_(m)— radical with m=1 or 2,or finally a

radical in which R³³ represents a hydrogen atom or an alkyl, -Σ-NR³⁴R³⁵or -Σ-CHR³⁶R³⁷ radical,

Σ representing a linear or branched alkylene radical containing 1 to 6carbon atoms, —R³⁴ and R³⁵ representing, independently, a hydrogen atomor an alkyl radical,

R³⁶ and R³⁷ representing, independently, a hydrogen atom or acarbocyclic or heterocyclic aryl radical optionally substituted by oneor more substituents chosen from the alkyl, OH, halogen, nitro, alkoxyor NR¹⁰R¹¹ radicals,

R¹⁰ and R¹¹ representing, independently, a hydrogen atom, an alkylradical or a —COR¹² group, or R¹⁰ and R¹¹ forming together with thenitrogen atom an optionally substituted heterocycle containing 4 to 7members and 1 to 3 heteroatoms including the nitrogen atom alreadypresent, the additional heteroatoms being chosen independently from thegroup constituted by the O, N and S atoms, said heterocycle being ableto be for example azetidine, pyrrolidine, piperidine, piperazine,morpholine or thiomorpholine,

R¹² representing a hydrogen atom or an alkyl, alkoxy or NR¹³R¹⁴ radical,

R¹³ and R¹⁴ representing, independently, a hydrogen atom or an alkylradical, or R¹³ and R¹⁴ forming together with the nitrogen atom anoptionally substituted heterocycle containing 4 to 7 members and 1 to 3heteroatoms including the nitrogen atom already present, the additionalheteroatoms being chosen independently from the group constituted by theO, N and S atoms, said heterocycle being able to be for exampleazetidine, pyrrolidine, piperidine, piperazine, morpholine orthiomorpholine, and T represents a —(CH₂)_(m)— radical with m=1 or 2,

or also A represents an alkyl, cycloalkyl or cycloalkylalkyl radical;

X represents S or NR³⁸,

R³⁸ representing a hydrogen atom or an alkyl, cyanoalkyl, aralkyl,alkylcarbonyl or aralkylcarbonyl radical,

Y represents O or S;

R¹ represents a hydrogen atom, an alkyl, aminoalkyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, trifluoromethylalkyl, alkenyl, allenyl,allenylalkyl, alkynyl, cyanoalkyl, —(CH₂)_(g)-Z¹R³⁹, —(CH₂)_(g)—COR⁴⁰,—(CH₂)_(g)—NHCOR⁷⁰, aryl, aralkyl, arylcarbonyl, heteroarylalkyl oraralkylcarbonyl radical, the aryl group of the aryl, aralkyl,arylcarbonyl, heteroarylalkyl or aralkylcarbonyl radicals itself beingoptionally substituted by one or more substituents chosen from the groupconstituted by the alkyl, halogen, alkoxy, nitro, cyano, cyanoalkyl,amino, alkylamino, dialkylamino, —(CH₂)_(k)-Z²R³⁹ or —(CH₂)_(k)—COR⁴⁰radicals,

Z¹ and Z² representing a bond, —O—, —NR⁴¹— or —S—,

R³⁹ and R⁴¹ representing, independently each time that they occur, ahydrogen atom or an alkyl, alkenyl, alkynyl or cyanoalkyl radical,

R⁴⁰ representing, independently each time that it occurs, a hydrogenatom or an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl, cyanoalkyl,alkoxy or NR⁴²R⁴³ radical,

R⁴² and R⁴³ representing, independently each time that they occur, ahydrogen atom or an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl orcyanoalkyl radical,

and R² represents a hydrogen atom, an alkyl aminoalkyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, trifluoromethylalkyl or —(CH₂)_(g)—NHCOR⁷¹radical, or also one of the aralkyl or heteroarylalkyl radicalsoptionally substituted on the aryl or heteroaryl group by one or more ofthe groups chosen independently from the group composed of a halogenatom and an alkyl, alkoxy, hydroxy, cyano, nitro, amino, alkylamino ordialkylamino radical,

R⁷⁰ and R⁷¹ representing independently an alkyl or alkoxy radical;

or R¹ and R², taken together with the carbon atom which carries them,form a carbocycle with 3 to 7 members;

B represents a hydrogen atom, an alkyl radical, a —(CH₂)_(g)-Z³R⁴⁴radical or a carbocyclic aryl radical optionally substituted 1 to 3times by the radicals chosen from the group composed of a halogen atom,a linear or branched alkyl or alkoxy radical containing 1 to 6 carbonatoms, a hydroxy, cyano or nitro radical, an amino, alkylamino ordialkylamino radical and a carbocyclic aryl radical,

Z³ representing a bond, —O—, —NR⁴⁵— or —S—,

R⁴⁴ and R⁴⁵ representing, independently, a hydrogen atom or an alkyl,alkenyl, alkynyl, alkoxy, allenyl, allenylalkyl or cyanoalkyl radical;

Ω represents one of the NR⁴⁶R⁴⁷ or OR⁴⁸ radicals, in which:

R⁴⁶ and R⁴⁷ represent, independently, a hydrogen atom or an alkyl,cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, allenyl, allenylalkyl,cyanoalkyl,  (CH₂)_(g)-Z⁴R⁵⁰, —(CH₂)_(k)—COR⁵¹, —(CH₂)_(k)—COOR⁵¹,—(CH₂)_(k)—CONHR⁵¹ or —SO₂R⁵¹ radical, or also a radical chosen from thearyl, aralkyl, aryloxyalkyl, arylcarbonyl, arylimino, aralkylcarbonyl,heteroaryl and in particular pyridinyl, pyridinylalkyl orpyridinylcarbonyl radicals, the aryl or heteroaryl group of said aryl,aralkyl, aryloxyalkyl, arylcarbonyl, arylimino, aralkylcarbonyl,heteroaryl, pyridinylalkyl or pyridinylcarbonyl radicals beingoptionally substituted by one or more substituents chosen independentlyfrom halogen, alkyl, alkoxy, hydroxy, nitro, cyano, cyanoalkyl, amino,alkylamino, dialkylamino, —(CH₂)_(k)-Z⁵R⁵⁰, —(CH₂)_(k)—COR⁵¹ and—(CH₂)_(k)—COOR⁵¹,

Z⁴ and Z⁵ representing a bond, —O—, —NR⁵²— or —S—,

or R⁴⁶ and R⁴⁷ taken together form with the nitrogen atom a non aromaticheterocycle with 4 to 8 members, the elements of the chain being chosenfrom a group composed of —CH(R⁵³)—, —NR⁵⁴—, —O—, —S— and —CO—, saidheterocycle being able to be for example an azetidine, a piperazine, ahomopiperazine, a 3,5-dioxopiperazine, a piperidine, a pyrrolidine, amorpholine or a thiomorpholine,

R⁵⁰ and R⁵², representing, independently each time that they occur, ahydrogen atom or an alkyl, alkenyl, alkynyl, allenyl, allenylalkyl orcyanoalkyl radical,

R⁵¹ representing, independently each time that they occur, a hydrogenatom, one of the cycloalkyl or cycloalkylalkyl radicals in which thecycloalkyl radical has 3 to 7 carbon atoms, a linear or branched alkylradical containing 1 to 8 carbon atoms, an alkenyl, alkynyl, allenyl,allenylalkyl, cyanoalkyl, alkoxyalkyl or NR⁵⁸R⁵⁹ radical, or also anaryl or aralkyl radical, said aryl or aralkyl radical being able to besubstituted by one or more of the substituents chosen independently froma halogen atom and an alkyl or alkoxy radical,

R⁵⁸ and R⁵⁹ representing, independently, a hydrogen atom or an alkyl,alkenyl, alkynyl, allenyl, allenylalkyl or cyanoalkyl radical,

R⁵³ and R⁵⁴ representing, independently, a hydrogen atom or a—(CH₂)_(k)-Z⁷R⁶⁰ or —(CH₂)_(k)—COR⁶¹ radical,

Z⁷ representing a bond, —O—, —NR⁶²— or —S—,

R⁶⁰ and R⁶² representing, independently, a hydrogen atom or an alkyl,alkenyl, allenyl, allenylalkyl, alkynyl, cyanoalkyl, aryl, aralkyl,arylcarbonyl, aralkylcarbonyl, pyridinyl, pyridinylalkyl orpyridinylcarbonyl radical, the aryl or pyridinyl group of the aryl,aralkyl, arylcarbonyl, aralkylcarbonyl, pyridinyl, pyridinylalkyl orpyridinylcarbonyl radicals being optionally substituted by one or moresubstituents chosen from the group constituted by the alkyl, halogen,nitro, alkoxy, cyano, cyanoalkyl, —(CH₂)_(k)-Z⁸R⁶³ and —(CH₂)_(k)—COR⁶⁴radicals,

R⁶¹ representing a hydrogen atom, an alkyl, allenyl, allenylalkyl,alkenyl, alkynyl, cyanoalkyl, alkoxy or NR⁶⁵R⁶⁶ radical,

R⁶⁵ and R⁶⁶ representing, independently, a hydrogen atom or an alkyl,allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radical,

Z⁸ representing a bond, —O—, —NR⁶⁷— or —S—,

R⁶³ and R⁶⁷ representing, independently, a hydrogen atom, an alkyl,allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radical,

R⁶⁴ representing a hydrogen atom, an alkyl, allenylalkyl, alkenyl,alkenyl, alkynyl, cyanoalkyl, alkoxy or NR⁶⁸R⁶⁹ radical,

R⁶⁸ and R⁶⁹ representing, independently, a hydrogen atom or an alkyl,allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radical,

and R⁴⁸ represents a hydrogen atom or an alkyl, alkynyl or cyanoalkylradical;

g and p, each time that they occur, being independently integers from 1to 6, and k and n, each time that they occur, being independentlyintegers from 0 to 6;

it being understood that when Het is such that the compound of generalformula (I) corresponds to general sub-formula (I)₄, then:

A represents the 4-hydroxy-2,3-di-tertiobutyl-phenyl radical;

B, R¹ and R² all represent H; and finally

Ω represents OH;

or pharmaceutically acceptable salts of the compounds of general formula(I);

can be used for preparing a medicament intended to have at least one ofthe following three activities:

-   -   to inhibit the monoamine oxydases, in particular monoamine        oxydase B,    -   to inhibit lipidic peroxidation,    -   to have a modulating activity vis-à-vis the sodium channels.

According to preferred variants of the invention, these compounds haveat least two of the activities mentioned above. In particular, theyinhibit both the MAO's and trap the ROS's or they will have both anantagonist activity vis-à-vis the sodium channels and a trappingactivity on the ROS's. In certain cases, the compounds of generalformula (I) even combine the three activities.

This allows the compounds of general formula (I) to be of use in thetreatment of the diseases mentioned previously such as being linked toMAO's, to lipidic peroxidation and to the sodium channels.

By alkyl, unless otherwise specified, is meant a linear or branchedalkyl radical containing 1 to 6 carbon atoms. By cycloalkyl, when nofurther detail is given, is meant a monocyclic carbon system containing3 to 7 carbon atoms. By alkenyl, when no further detail is given, ismeant a linear or branched alkyl radical containing 1 to 6 carbon atomsand having at least one unsaturation (double bond). By alkynyl, when nofurther detail is given, is meant a linear or branched alkyl radicalcontaining 1 to 6 carbon atoms and having at least one doubleunsaturation (triple bond). By allenyl, is meant the —CH═C═CH₂ radical.By carbocyclic or heterocyclic aryl, is meant a carbocyclic system (inparticular, the phenyl radical which can be noted Ph in an abbreviatedfashion) or heterocyclic system comprising at least one aromatic ring, asystem being called heterocyclic when at least one of the rings whichcomprises it contains a heteroatom (O, N or S). By heterocycle, is meanta mono- or polycyclic system, said system comprising at least oneheteroatom chosen from O, N and S and being saturated, partially ortotally unsaturated or aromatic. By heteroaryl, is meant a heterocycleas defined previously in which at least one of the rings which comprisesit is aromatic. By haloalkyl, is meant an alkyl radical at least one ofhydrogen atoms of which (and optionally all) is replaced by a halogenatom.

Moreover, by an optionally substituted radical is meant unless otherwisespecified a radical comprising one or more substituents chosenindependently from the group composed of a halogen atom and the alkyland alkoxy radicals.

By alkylthio, alkoxy, haloalkyl, alkoxyalkyl, trifluoromethylalkyl,cycloalkylalkyl, haloalkoxy, aminoalkyl, alkenyl, alkynyl, allenylalkyl,cyanoalkyl and aralkyl radicals, is meant respectively the alkylthio,alkoxy, haloalkyl, alkoxyalkyl, trifluoromethylalkyl, cycloalkylalkyl,haloalkoxy, aminoalkyl, alkenyl, alkynyl, allenylalkyl, cyanoalkyl andaralkyl radicals the alkyl radical (the alkyl radicals) of which havethe meaning(s) indicated previously.

By heterocycle, is meant in particular the thiophene, piperidine,piperazine, quinoline, indoline and indole radicals. By linear orbranched alkyl having 1 to 6 carbon atoms, is meant in particular themethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl andtert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals.Finally, by halogen, is meant the fluorine, chlorine, bromine or iodineatoms.

Preferably, the compounds according to the invention are such that theycorrespond to general formula (I):

in racemic, enantiomeric form or any combination of these forms, inwhich Het is a heterocycle with 5 members comprising 2 heteroatoms andsuch that general formula (I) corresponds exclusively to one of thefollowing sub-formulae:

in whichA representseither a

radical in which R³ represents a hydrogen atom, the OH group or analkoxy or alkyl radical,or a

radical in which R⁴, R⁵, R⁶, R⁷ and R⁸ represent, independently, ahydrogen atom, a halogen, the OH group or an alkyl, alkoxy, cyano, nitroor NR¹⁰R¹¹ radical,R¹⁰ and R¹¹ representing, independently, a hydrogen atom or an alkylradicalR⁹ represents a hydrogen atom or an alkyl radical, and W doesn't exist,or represents a bond, or —O—, —S— or —NR¹⁸—, in which R¹⁸ represents ahydrogen atom or an alkyl radical;or a

radical in which Q represents H, —OR²², —SR²², —NR²³R²⁴, a phenylradical optionally substituted by one or more substituents chosenindependently from a halogen atom, an OH, cyano, nitro, alkyl, alkoxy or—NR¹⁰R¹¹ radical and a group with two substituents representing togethera methylenedioxy or ethylenedioxy radical, or also Q represents a —COPh,—OPh, —SPh, —SO₂Ph or —CH₂Ph radical, said —COPh, —OPh, —SPh, —SO₂Ph or—CH₂Ph radical being optionally substituted on its aromatic part by oneor more of the substituents chosen independently from an alkyl or alkoxyradical and a halogen atom, R¹⁰ and R¹¹ representing, independently, ahydrogen atom or an alkyl radical, or R¹⁰ and R¹¹ forming together withthe nitrogen atom an optionally substituted heterocycle containing 4 to7 members and 1 to 3 heteroatoms including the nitrogen atom alreadypresent, the additional heteroatoms being chosen independently from thegroup constituted by the O, N and S atoms, said heterocycle being ableto be for example azetidine, pyrrolidine, piperidine, piperazine,morpholine or thiomorpholine,R²² representing a hydrogen atom, an alkyl radical or an aryl radicaloptionally substituted by one or more substituents chosen from thealkyl, OH, halogen, nitro and alkoxy radicals,R²³ and R²⁴ representing, independently, a hydrogen atom, an alkylradical or a —CO—R²⁵ radical,R²⁵ representing an alkyl radical,and R¹⁹, R²⁰ and R²¹ represent, independently, a hydrogen, a halogen,the OH or SR²⁶ group, or an alkyl, cycloalkyl, alkenyl, alkoxy, cyano,nitro, —SO₂NHR⁴⁹, —CONHR⁵⁵, —S(O)_(q)R⁵⁶, —NH(CO)R⁵⁷, —CF₃, —OCF₃ orNR²⁷R²⁸ radical, R²⁶ representing a hydrogen atom or an alkyl radical,R²⁷ and R²⁸ representing, independently, a hydrogen atom, an alkylradical or a —COR²⁹ group, or R²⁷ and R²⁸ forming together with thenitrogen atom an optionally substituted heterocycle containing 4 to 7members and 1 to 3 heteroatoms including the nitrogen atom alreadypresent, the additional heteroatoms being chosen independently from thegroup constituted by the O, N and S atoms, said heterocycle being ableto be for example azetidine, pyrrolidine, piperidine, piperazine,morpholine or thiomorpholine,R⁴⁹ and R⁵⁵ representing, independently each time that they occur, ahydrogen atom or an alkyl or alkylcarbonyl radical,q representing an integer from 0 to 2,R⁵⁶ and R⁵⁷ representing, independently each time that they occur, ahydrogen atom or an alkyl or alkoxy radical,R²⁹ representing a hydrogen atom, an alkyl, alkoxy or —NR³⁰R³¹ radical,R³⁰ and R³¹ representing, independently, a hydrogen atom or an alkylradical, or R³⁰ and R³¹ forming together with the nitrogen atom anoptionally substituted heterocycle containing 4 to 7 members and 1 to 3heteroatoms including the nitrogen atom already present, the additionalheteroatoms being chosen independently from the group constituted by theO, N and S atoms, said heterocycle being able to be for exampleazetidine, pyrrolidine, piperidine, piperazine, morpholine orthiomorpholine,or a

radical in which R³² represents a hydrogen atom or an alkyl radical, andT represents a —(CH₂)_(m)— radical with m=1 or 2,or finally a

radical in which R³³ represents a hydrogen atom or an alkyl, -Σ-NR³⁴R³⁵or -Σ-CHR³⁶R³⁷ radical,Σ representing a linear or branched alkylene radical containing 1 to 6carbon atoms,R³⁴ and R³⁵ representing, independently, a hydrogen atom or an alkylradical,R³⁶ and R³⁷ representing, independently, a hydrogen atom or acarbocyclic or heterocyclic aryl radical optionally substituted by oneor more substituents chosen from the alkyl, OH, halogen, nitro, alkoxyor NR¹⁰R¹¹ radicals,R¹⁰ and R¹¹ representing, independently, a hydrogen atom, an alkylradical, or R¹⁰ and R¹¹ forming together with the nitrogen atom anoptionally substituted heterocycle containing 4 to 7 members and 1 to 3heteroatoms including the nitrogen atom already present, the additionalheteroatoms being chosen independently from the group constituted by theO, N and S atoms, said heterocycle being able to be for exampleazetidine, pyrrolidine, piperidine, piperazine, morpholine orthiomorpholine,and T represents a —(CH₂)_(m)— radical with m=1 or 2,or also A represents an alkyl, cycloalkyl or cycloalkylalkyl radical;X represents S or NR³⁸,R³⁸ representing a hydrogen atom or an alkyl, cyanoalkyl, aralkyl,alkylcarbonyl or aralkylcarbonyl radical,Y represents O or S;R¹ represents a hydrogen atom, an alkyl, aminoalkyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, trifluoromethylalkyl, alkenyl, allenyl,allenylalkyl, alkynyl, cyanoalkyl, —(CH—)_(g)-Z¹R³⁹, —(CH₂)_(g)—COR⁴⁰,—(CH₂)_(g)—NHCOR⁷⁰, aryl, aralkyl, arylcarbonyl, heteroarylalkyl oraralkylcarbonyl radical, the aryl group of the aryl, aralkyl,arylcarbonyl, heteroarylalkyl or aralkylcarbonyl radicals itself beingoptionally substituted by one or more substituents chosen from the groupconstituted by the alkyl, halogen, alkoxy, nitro, cyano, cyanoalkyl,amino, alkylamino, dialkylamino, —(CH₂)_(k)-Z²R³⁹ or —(CH₂)_(k)—COR⁴⁰radicals,Z¹ and Z² representing a bond, —O—, —NR⁴¹— or —S—,R³⁹ and R⁴¹ representing, independently each time that they occur, ahydrogen atom or an alkyl, alkenyl, alkynyl or cyanoalkyl radical,R⁴⁰ representing, independently each time that it occurs, a hydrogenatom or an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl, cyanoalkyl,alkoxy or NR⁴²R⁴³ radical,R⁴² and R⁴³ representing, independently each time that they occur, ahydrogen atom or an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl orcyanoalkyl radical,and R² represents a hydrogen atom, an alkyl, aminoalkyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, trifluoromethylalkyl or —(CH₂)_(g)—NHCOR⁷¹radical, or also one of the aralkyl or heteroarylalkyl radicalsoptionally substituted on the aryl or heteroaryl group by one or more ofthe groups chosen independently from the group composed of a halogenatom and an alkyl, alkoxy, hydroxy, cyano, nitro, amino, alkylamino ordialkylamino radical,R⁷⁰ and R⁷ representing independently an alkyl or alkoxy radical;or R¹ and R², taken together with the carbon atom which carries them,form a carbocycle with 3 to 7 members;B represents a hydrogen atom, an alkyl radical, a —(CH₂)_(g)-Z³R⁴⁴radical or a carbocyclic aryl radical optionally substituted 1 to 3times by the radicals chosen from the group composed of a halogen atom,a linear or branched alkyl or alkoxy radical containing 1 to 6 carbonatoms, a hydroxy, cyano or nitro radical, an amino, alkylamino ordialkylamino radical and a carbocyclic aryl radical,Z³ representing a bond, —O—, —NR⁴⁵— or —S—,R⁴⁴ and R⁴⁵ representing, independently, a hydrogen atom or an alkyl,alkenyl, alkynyl, allenyl, allenylalkyl or cyanoalkyl radical;Ω represents one of the NR⁴⁶R⁴⁷ or OR⁴⁸ radicals, in which:R⁴⁶ and R⁴⁷ represent, independently, a hydrogen atom or an alkyl,cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, allenyl, allenylalkyl,cyanoalkyl, —(CH)_(g)-Z⁴R⁵⁰, —(CH₂)_(k)—COR⁵¹, —(CH₂)_(k)—COOR⁵¹,—(CH₂)_(k)—CONHR⁵¹ or —SO₂R⁵¹ radical, or also a radical chosen from thearyl, aralkyl, aryloxyalkyl, arylcarbonyl, arylimino, aralkylcarbonyl,heteroaryl and in particular pyridinyl, pyridinylalkyl orpyridinylcarbonyl radicals, the aryl or heteroaryl group of said aryl,aralkyl, aryloxyalkyl, arylcarbonyl, arylimino, aralkylcarbonyl,heteroaryl, pyridinylalkyl or pyridinylcarbonyl radicals beingoptionally substituted by one or more substituents chosen independentlyfrom halogen, alkyl, alkoxy, hydroxy, nitro, cyano, cyanoalkyl, amino,alkylamino, dialkylamino, —(CH₂)_(k)-Z⁵R⁵⁰, —(CH₂)_(k)—COR⁵¹ and—(CH₂)_(k)—COOR⁵¹,Z⁴ and Z⁵ representing a bond, —O—, —NR⁵²— or —S—,or R⁴⁶ and R⁴⁷ taken together form with the nitrogen atom a non aromaticheterocycle with 4 to 8 members, the elements of the chain being chosenfrom a group composed of —CH(R⁵³)—, —NR⁵⁴—, —O—, —S— and —CO—, saidheterocycle being able to be for example an azetidine, a piperazine, ahomopiperazine, a 3,5-dioxopiperazine, a piperidine, a pyrrolidine, amorpholine or a thiomorpholine,R⁵⁰ and R⁵², representing, independently each time that they occur, ahydrogen atom or an alkyl, alkenyl, alkynyl, alkoxy, allenyl,allenylalkyl or cyanoalkyl radical,R⁵¹ representing, independently each time that they occur, a hydrogenatom, one of the cycloalkyl or cycloalkylalkyl radicals in which thecycloalkyl radical has 3 to 7 carbon atoms, a linear or branched alkylradical containing 1 to 8 carbon atoms, an alkenyl, alkynyl, allenyl,allenylalkyl, cyanoalkyl, alkoxyalkyl or NR⁵⁸R⁵⁹ radical, or also anaryl or aralkyl radical, said aryl or aralkyl radical being able to besubstituted by one or more of the substituents chosen independently froma halogen atom and an alkyl or alkoxy radical,R⁵⁸ and R⁵⁹ representing, independently, a hydrogen atom or an alkyl,alkenyl, alkynyl, allenyl, allenylalkyl or cyanoalkyl radical,R⁵³ and R⁵⁴ representing, independently, a hydrogen atom or a—(CH₂)_(k)-Z⁷R⁶⁰ or —(CH₂))_(k)—COR⁶¹ radical,Z⁷ representing a bond, —O—, —NR⁶²— or —S—,R⁶⁰ and R⁶² representing, independently, a hydrogen atom or an alkyl,alkenyl, allenyl, allenylalkyl, alkynyl, cyanoalkyl, aryl, aralkyl,arylcarbonyl, aralkylcarbonyl, pyridinyl, pyridinylalkyl orpyridinylcarbonyl radical, the aryl or pyridinyl group of the aryl,aralkyl, arylcarbonyl, aralkylcarbonyl, pyridinyl, pyridinylalkyl orpyridinylcarbonyl radicals being optionally substituted by one or moresubstituents chosen from the group constituted by the alkyl, halogen,nitro, alkoxy, cyano, cyanoalkyl, —(CH₂)_(k)-Z⁸R⁶³ and —(CH₂)_(k)—COR⁶⁴radicals,R⁶¹ representing a hydrogen atom, an alkyl, allenyl, allenylalkyl,alkenyl, alkynyl, cyanoalkyl, alkoxy or NR⁶⁵R⁶⁶ radical,R⁶⁵ and R⁶⁶ representing, independently, a hydrogen atom or an alkyl,allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radical,Z⁸ representing a bond, —O—, —NR⁶⁷— or —S—,R⁶³ and R⁶⁷ representing, independently, a hydrogen atom, an alkyl,allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radical,R⁶⁴ representing a hydrogen atom, an alkyl, allenylalkyl, alkenyl,alkenyl, alkynyl, cyanoalkyl, alkoxy or NR⁶⁸R⁶⁹ radical,R⁶⁸ and R⁶⁹ representing, independently, a hydrogen atom or an alkyl,allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radical,g and p, each time that they occur, being independently integers from 1to 6, and k and n, each time that they occur, being independentlyintegers from 0 to 6;and R⁴⁸ represents a hydrogen atom or an alkyl alkynyl or cyanoalkylradical;it being understood that when Het is such that the compound of generalformula (I) corresponds to general sub-formula (I)₄, then:A exclusively represents the 4-hydroxy-2,3-di-tertiobutyl-phenylradical;B represents H,R¹ and R² both represent H; and finallyΩ represents OH;or salts of said compounds

According to the invention, there will Generally be preferred thecompounds of general formula (I) in which at least one of the followingradicals is found:

-   -   A representing:        -   either the        -   radical in which R³ represents a hydrogen atom, the OH group            or an alkoxy or alkyl radical,        -   or the        -   radical in which R⁴, R⁵, R⁶, R⁷ and R⁸ represent,            independently, a hydrogen atom, the OH group or an alkyl or            alkoxy radical,        -   R⁹ represents a hydrogen atom or an alkyl radical,        -   and W does not exist, or represents a bond, —O—, —S— or            —NR¹⁸—, R¹⁸ representing a hydrogen atom or an alkyl            radical;        -   or the        -   radical in which Q represents H, —OR²², —SR²² or a phenyl            radical optionally substituted by one substituent or            substituents chosen independently from a halogen atom, an            OH, cyano, nitro, alkyl, alkoxy or —NR¹⁰R¹¹ radical and a            group of two substituents together representing a            methylenedioxy or ethylenedioxy radical, or also Q            represents an —OPh, —SPh, —SO₂Ph or —CH₂Ph radical, said            —OPh, —SPh, —SO₂Ph or —CH₂Ph radical being optionally            substituted on its aromatic part by a substituent or            substituents chosen from an alkyl or alkoxy radical and a            halogen atom,        -   R¹⁰ and R¹¹ representing, independently, a hydrogen atom or            an alkyl radical;        -   R²² representing a hydrogen atom, an alkyl radical or an            aryl radical optionally substituted by one or more            substituents chosen from the alkyl, OH, halogen, nitro and            alkoxy radicals,        -   and R¹⁹, R²⁰ and R²¹ represent, independently, a hydrogen, a            halogen, the OH or SR²⁶ group, or an alkyl, cycloalkyl,            alkenyl, alkoxy, cyano, nitro, —SO₂NHR⁴⁹, —CONHR⁵⁵,            S(O)_(q)R⁵⁶, —N(CO)R⁵⁷, —CF₃, —OCF₃ or NR²⁷R²⁸ radical,        -   R²⁶ representing a hydrogen atom or an alkyl radical,        -   R²⁷ and R²⁸ representing, independently, a hydrogen atom, an            alkyl radical or a —COR²⁹ group, or also R²⁷ and R²⁸ forming            together with the nitrogen atom which carries them a            heterocycle with 5 to 6 members chosen from —CH₂—, —NH— and            —O—,        -   R⁴⁹ and R⁵⁵ representing, independently each time that they            occur, a hydrogen atom or an alkyl or alkylcarbonyl radical,        -   q representing an integer from 0 to 2,        -   R⁵⁶ and R⁵⁷ representing, independently each time that they            occur, a hydrogen atom or an alkyl or alkoxy radical,        -   R²⁹ representing a hydrogen atom, an alkyl, alkoxy or            —NR³⁰R³¹ radical,        -   R³⁰ and R³¹ representing, independently, a hydrogen atom or            an alkyl radical,        -   or the        -   radical in which R³² represents a hydrogen atom or an alkyl            radical, and T represents the —(CH₂)₂— radical        -   or finally the        -   radical in which R³³ represents a hydrogen atom or an alkyl,            -Σ-NR³⁴R³⁵ or -Σ-CHR³⁶R³⁷ radical,        -   Σ representing a linear or branched alkylene radical            containing 1 to 6 carbon atoms,        -   R³⁴ and R³⁵ representing, independently, a hydrogen atom or            an alkyl radical,        -   R³⁶ and R³⁷ representing, independently, a hydrogen atom or            a carbocyclic or heterocyclic aryl radical optionally            substituted by one or more substituents chosen from the            alkyl, OH, halogen, nitro, alkoxy or NR¹⁰R¹¹ radicals,        -   R¹⁰ and R¹¹ representing, independently, a hydrogen atom, an            alkyl radical or a —COR¹² group, or R¹⁰ and R¹¹ forming            together with the nitrogen atom an optionally substituted            heterocycle containing 4 to 7 members and 1 to 3 heteroatoms            including the nitrogen atom already present, the additional            heteroatoms being chosen independently from the group            constituted by the O, N and S atoms, said heterocycle being            able to be for example azetidine, pyrrolidine, piperidine,            piperazine, morpholine or thiomorpholine,        -   R¹² representing a hydrogen atom or an alkyl, alkoxy or            NR¹³R¹⁴ radical,        -   R¹³ and R¹⁴ representing, independently, a hydrogen atom or            an alkyl radical, or R¹³ and R¹⁴ forming together with the            nitrogen atom an optionally substituted heterocycle            containing 4 to 7 members and 1 to 3 heteroatoms including            the nitrogen atom already present, the additional            heteroatoms being chosen independently from the group            constituted by the O, N and S atoms, such as for example            azetidine, pyrrolidine, piperidine, piperazine, morpholine            or thiomorpholine,        -   and T represents the —(CH₂)— radical;    -   Ω representing:        -   either the NR⁴⁶R⁴⁷ radical in which R⁴⁶ and R⁴⁷ represent,            independently, a hydrogen atom or an alkyl, cycloalkyl,            cycloalkylalkyl, alkenyl, alkynyl, allenyl, allenylalkyl,            cyanoalkyl, —(CH₂)_(k)—COR⁵¹, —COOR⁵¹ or —SO₂R⁵¹ radical or            also a radical chosen from the aryl, aralkyl, aryloxyalkyl,            arylcarbonyl, arylimino, aralkylcarbonyl, heteroaryl            radicals and in particular pyridinyl, pyridinylalkyl or            pyridinylcarbonyl, the aryl or heteroaryl group of said            aryl, aralkyl, aryloxyalkyl, arylcarbonyl, arylimino,            aralkylcarbonyl, heteroaryl, pyridinylalkyl or            pyridinylcarbonyl radicals being optionally substituted by a            substituent or substituents chosen independently from            halogen, alkyl, alkoxy, hydroxy, nitro, cyano, cyanoalkyl,            amino, alkylamino, dialkylamino, —(CH₂)_(k)-Z⁵R⁵⁰,            —(CH₂)_(k)—COR⁵¹ and —(CH₂)_(k)—COOR⁵¹,        -   R⁵¹ representing a hydrogen atom or an alkyl, alkenyl,            alkynyl or alkoxyalkyl radical        -   or the OH radical;

Moreover, when A represents the

radical, the Q radical is preferably found in para position with respectto the heterocycle Het.

Generally, all the preferences relating to sub-groups of compounds ofgeneral formula (I) presented below remain applicable with respect tothe use of compounds of general formula (I) as defined previously forthe preparation of medicaments intended to inhibit monoamine oxidases,in particular monoamine oxidase B, to inhibit lipidic peroxidation, tohave a modulatory activity on the sodium channels or to have two of thethree activities or the three activities mentioned previously.

According to a particular variant of the invention, the compounds ofgeneral formula (I) or their salts are more especially intended to havean inhibitory activity on MAO's and/or ROS's and they will therefore bepreferably such that:

A represents

either a

radical in which R³ represents a hydrogen atom, the OH group or analkoxy or alkyl radical,or a

radical in which R⁴, R⁵, R⁶, R⁷ and R⁸ represent, independently, ahydrogen atom, a halogen, the OH group or an alkyl, alkoxy or NR¹⁰R¹¹radical,R¹⁰ and R¹¹ representing, independently, a hydrogen atom or an alkylradical, or R¹⁰ and R¹¹ forming together with the nitrogen atom anoptionally substituted heterocycle containing 4 to 7 members and 1 to 3heteroatoms including the nitrogen atom already present, the additionalheteroatoms being chosen independently from the group constituted by theO, N and S atoms, said heterocycle being able to be for exampleazetidine, pyrrolidine, piperidine, piperazine, morpholine orthiomorpholine,R⁹ represents a hydrogen atom or an alkyl radical,and W doesn't exist, or represents a bond, or —O—, —S— or —NR¹⁸—, inwhich R¹⁸ represents a hydrogen atom or an alkyl radical;or a

radical in which Q represents —OR²²—, —SR²², —NR²³R²⁴, a phenyl radicaloptionally substituted by one or more of the substituents chosenindependently from a halogen atom and an OH, cyano, nitro, alkyl, alkoxyor —NR¹⁰R¹¹ radical,R¹⁰ and R¹¹ representing, independently, a hydrogen atom or an alkylradical, or R¹⁰ and R¹¹ forming together with the nitrogen atom anoptionally substituted heterocycle containing 4 to 7 members and 1 to 3heteroatoms including the nitrogen atom already present, the additionalheteroatoms being chosen independently from the group constituted by theO, N and S atoms, said heterocycle being able to be for exampleazetidine, pyrrolidine, piperidine, piperazine, morpholine orthiomorpholine,R²² representing a hydrogen atom, an alkyl radical or an aryl radicaloptionally substituted by one or more substituents chosen from thealkyl, OH, halogen, nitro and alkoxy radicals,R²³ and R²⁴ representing, independently, a hydrogen atom or an alkylradical,and R¹⁹, R²⁰ and R²¹ represent, independently, a hydrogen, a halogen,the OH or SR²⁶ group, or an alkyl, alkenyl, alkoxy or NR²⁷R²⁸ radical,R²⁶ representing a hydrogen atom or an alkyl radical,R²⁷ and R²⁸ representing, independently, a hydrogen atom or an alkylradical, or R²⁷ and R²⁸ forming together with the nitrogen atom anoptionally substituted heterocycle containing 4 to 7 members and 1 to 3heteroatoms including the nitrogen atom already present, the additionalheteroatoms being chosen independently from the group constituted by theO, N and S atoms; said heterocycle being able to be for exampleazetidine, pyrrolidine, piperidine, piperazine, morpholine orthiomorpholine,or a

radical in which R³² represents a hydrogen atom or an alkyl radical,and T represents a —(CH₂)_(m)— radical with m=1 or 2,or finally a

radical in which R³³ represents a hydrogen atom or an alkyl, -Σ-NR³⁴R³⁵or -Σ-CHR³⁶R³⁷ radical,Σ representing a linear or branched alkylene radical containing 1 to 6carbon atoms,R³⁴ and R³⁵ representing, independently, a hydrogen atom or an alkylradical,R³⁶ and R³⁷ representing, independently, a hydrogen atom or acarbocyclic or heterocyclic aryl radical optionally substituted by oneor more substituents chosen from the alkyl, OH, halogen, nitro, alkoxyor NR¹⁰R¹¹ radicals,R¹⁰ and R¹¹ representing, independently, a hydrogen atom or an alkylradical, or R¹⁰ and R¹¹ forming together with the nitrogen atom anoptionally substituted heterocycle containing 4 to 7 members and 1 to 3heteroatoms including the nitrogen atom already present, the additionalheteroatoms being chosen independently from the group constituted by theO, N and S atoms, said heterocycle being able to be for exampleazetidine, pyrrolidine, piperidine, piperazine, morpholine orthiomorpholine, and T represents a —(CH₂)_(m)— radical with m=1 or 2,X represents S or NR³⁸,R³⁸ representing a hydrogen atom or an alkyl or cyanoalkyl radical,Y represents O or S;R¹ represents a hydrogen atom, an alkyl, cycloalkyl, alkenyl, allenyl,allenylalkyl, alkynyl, cyanoalkyl, —(CH₂)_(g)-Z¹R³⁹, —(CH₂)_(g)—COR⁴⁰,aryl, aralkyl, arylcarbonyl, or aralkylcarbonyl radical, the aryl groupof the aryl, aralkyl, arylcarbonyl, or aralkylcarbonyl radicals beingitself optionally substituted by a substituent or substituents chosenfrom the group constituted by the alkyl, halogen, alkoxy, nitro, cyano,cyanoalkyl, —(CH₂)_(k)-Z²R³⁹ or —(CH₂)_(k)—COR⁴⁰ radicals,Z¹ and Z² representing a bond, —O—, —NR⁴¹— or —S—,R³⁹ and R⁴¹ representing, independently each time that they occur, ahydrogen atom or an alkyl, alkenyl, alkynyl, alkoxy or cyanoalkylradical,R⁴⁰ representing, independently each time that it occurs, a hydrogenatom or an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl, cyanoalkyl,alkoxy or NR⁴²R⁴³ radical,R⁴² and R⁴³ representing, independently each time that they occur, ahydrogen atom or an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl orcyanoalkyl radical,and R² represents a hydrogen atom or an alkyl radicalB represents a hydrogen atom or a —(CH₂)_(g)-Z³R⁴⁴ radical,Z³ representing a bond, —O—, —NR⁴⁵— or —S—,R⁴⁴ and R⁴⁵ representing, independently, a hydrogen atom or an alkyl,alkenyl, alkynyl, allenyl, allenylalkyl or cyanoalkyl radical;Ω represents one of the NR⁴⁶R⁴⁷ or OR⁴⁸ radicals, in which:R⁴⁶ and R⁴⁷ represent, independently, a hydrogen atom or an alkyl,cycloalkyl, alkenyl, alkynyl, allenyl, allenylalkyl, cyanoalkyl,—(CH₂)_(g)-Z⁴R⁵⁰ pr —(CH₂)_(k)—COR⁵¹ radical, or also a radical chosenfrom the aryl, aralkyl, arylcarbonyl, aralkylcarbonyl, pyridinyl,pyridinylalkyl or pyridinylcarbonyl radicals, the aryl or heteroarylgroup of said aryl, aralkyl, arylcarbonyl, aralkylcarbonyl,pyridinylalkyl or pyridinylcarbonyl radicals being optionallysubstituted by one or more of the substituents chosen independently fromhalogen, alkyl, alkoxy, nitro, cyano, cyanoalkyl, amino, alkylamino,dialkylamino, —(CH₂)_(k)-Z⁵R⁵⁰, —(CH₂)_(k)—COR⁵¹ and —(CH₂)_(k)—COOR⁵¹,Z⁴ and Z⁵ representing a bond, —O—, —NR⁵²— or —S—,or R⁴⁶ and R⁴⁷ taken together form with the nitrogen atom a non aromaticheterocycle with 4 to 8 members, the elements of the chain being chosenfrom a group composed of —CH(R⁵³)—, —NR⁵⁴—, —O—, —S— and —CO—, saidheterocycle being able to be for example an azetidine, a piperazine, ahomopiperazine, a 3,5-dioxopiperazine, a piperidine, a pyrrolidine, amorpholine or a thiomorpholine,R⁵⁰ and R⁵², representing, independently each time that they occur, ahydrogen atom or an alkyl, alkenyl, alkynyl, allenyl, allenylalkyl orcyanoalkyl radical,R⁵¹ representing, independently each time that they occur, a hydrogenatom, a linear or branched alkyl radical containing 1 to 8 carbon atoms,an alkenyl, alkynyl, allenyl, allenylalkyl, cyanoalkyl or NR⁵⁸R⁵⁹radical,R⁵⁸ and R⁵⁹ representing, independently, a hydrogen atom or an alkyl,alkenyl, alkynyl, alkoxy, allenyl, allenylalkyl or cyanoalkyl radical,R⁵³ and R⁵⁴ representing, independently, a hydrogen atom or a—(CH₂)_(k)-Z⁷R⁶⁰ or —(CH₂)_(k)—COR⁶¹ radical,Z⁷ representing a bond, —O—, —NR⁶²— or —S—,R⁶⁰ and R⁶² representing, independently, a hydrogen atom or an alkyl,alkenyl, allenyl, allenylalkyl, alkynyl, cyanoalkyl, aryl, aralkyl,arylcarbonyl, aralkylcarbonyl, pyridinyl, pyridinylalkyl orpyridinylcarbonyl radical, the aryl or pyridinyl group of the aryl,aralkyl, arylcarbonyl, aralkylcarbonyl, pyridinyl, pyridinylalkyl orpyridinylcarbonyl radicals being optionally substituted by one or moresubstituents chosen from the group constituted by the alkyl, halogen,nitro, alkoxy, cyano, cyanoalkyl, —(CH—)_(k)-Z⁸R⁶³ and —(CH₂)_(k)—COR⁶⁴radicals,R⁶¹ representing a hydrogen atom, an alkyl, allenyl, allenylalkyl,alkenyl, alkynyl, cyanoalkyl, alkoxy or NR⁶⁵R⁶⁶ radical,R⁶⁵ and R⁶⁶ representing, independently, a hydrogen atom or an alkyl,allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radical,Z⁸ representing a bond, —O—, —NR⁶⁷— or —S—,R⁶³ and R⁶⁷ representing, independently, a hydrogen atom, an alkyl,allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radical,R⁶⁴ representing a hydrogen atom, an alkyl, allenylalkyl, alkenyl,alkenyl, alkynyl, cyanoalkyl, alkoxy or NR⁶⁸R⁶⁹ radical,R⁶⁸ and R⁶⁹ representing, independently, a hydrogen atom or an alkyl,allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radical,and R⁴⁸ represents a hydrogen atom or an alkyl, alkynyl or cyanoalkylradical;g and p, each time that they occur, being independently integers from 1to 6, and k and n, each time that they occur, being independentlyintegers from 0 to 6.

More preferentially, the compounds of general formula (I) (or theirsalts), when they are intended to have an inhibitory activity on MAO'sand/or ROS's, will be such that:

A represents

either a

radical in which R³ represents a hydrogen atom, the OH group or analkoxy or alkyl radical,or a

radical in which R⁴, R⁵, R⁶, R⁷ and R⁸ represent, independently, ahydrogen atom, or an alkyl or alkoxy radical,R⁹ represents a hydrogen atom,and W doesn't exist, or represents a bond, or —O—, —S— or —NR¹⁸—, inwhich R¹⁸ represents a hydrogen atom or an alkyl radical;or a

radical in which Q represents —OR²², —SR²² or a phenyl radicalsubstituted by an OH radical and optionally one or more of theadditional substituents chosen independently from a halogen atom and anOH, alkyl or alkoxy radical.R²² representing a hydrogen atom or an alkyl radical,and R¹⁹, R²⁰ and R²¹ represent, independently, a hydrogen, a halogen,the OH or SR²⁶ group, or an alkyl or alkoxy radical,R²⁶ representing a hydrogen atom or an alkyl radical,or a

radical in which R³² represents a hydrogen atom or an alkyl radical,and T represents a —(CH₂)_(m)— radical with m=1 or 2,or finally a

radical in which R³³ represents a hydrogen atom or an alkyl, -Σ-NR³⁴R³⁵or -Σ-CHR³⁶R³⁷ radical,Σ representing a linear or branched alkylene radical containing 1 to 6carbon atoms,R³⁴ and R³⁵ representing, independently, a hydrogen atom or an alkylradical,R³⁶ and R³⁷ representing, independently, a hydrogen atom or acarbocyclic or heterocyclic aryl radical optionally substituted by oneor more substituents chosen from the alkyl, OH, halogen, nitro or alkoxyradicals,and T represents a —(CH₂)_(m)— radical with m=1 or 2,X represents S or NR³,R³⁸ representing a hydrogen atom or an alkyl or cyanoalkyl radical,Y represents O or S;R¹ represents a hydrogen atom, an alkyl, cycloalkyl, alkenyl, allenyl,allenylalkyl, alkynyl, cyanoalkyl, —(CH₂)_(g)-Z¹R³⁹, —(CH₂)_(g)—COR⁴⁰,aryl, aralkyl, arylcarbonyl, or aralkylcarbonyl radical, the aryl groupof the aryl, aralkyl, arylcarbonyl, or aralkylcarbonyl radicals beingitself optionally substituted by one or more substituents chosen fromthe group constituted by the alkyl, halogen, alkoxy, nitro, cyano,cyanoalkyl, —(CH₂)_(k)-Z²R³⁹ or —(CH₂)_(k)—COR⁴⁰ radicals,Z¹ and Z² representing a bond, —O—, —NR⁴¹— or —S—,R³⁹ and R⁴¹ representing, independently each time that they occur, ahydrogen atom or an alkyl, alkenyl, alkynyl or cyanoalkyl radical,R⁴⁰ representing, independently each time that it occurs, a hydrogenatom or an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl, cyanoalkyl,alkoxy or NR⁴²R⁴³ radical,R⁴² and R⁴³ representing, independently each time that they occur, ahydrogen atom or an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl orcyanoalkyl radical,and R² represents a hydrogen atom or an alkyl radicalB represents a hydrogen atom or a —(CH₂)_(g)-Z³R⁴⁴ radical,Z₃ representing a bond, —O—, —NR⁴⁵— or —S—,R⁴⁴ and R⁴⁵ representing, independently, a hydrogen atom or an alkyl,alkenyl, alkynyl, allenyl, allenylalkyl or cyanoalkyl radical;Ω represents one of the NR⁴⁶R⁴⁷ or OR⁴⁸ radicals, in which:R⁴⁶ and R⁴⁷ represent, independently, a hydrogen atom or an alkyl,cycloalkyl, alkenyl, alkynyl, allenyl, allenylalkyl, cyanoalkyl,—(CH₂)_(g)-Z⁴R⁵⁰ or —(CH₂)_(k)—COR⁵¹ radical or also a radical chosenfrom the aryl, aralkyl, arylcarbonyl, aralkylcarbonyl, pyridinyl,pyridinylalkyl or pyridinylcarbonyl radicals, the aryl or heteroarylgroup of said aryl, aralkyl, arylcarbonyl, aralkylcarbonyl,pyridinylalkyl or pyridinylcarbonyl radicals being optionallysubstituted by one or more of the substituents chosen independently fromhalogen, alkyl, alkoxy, nitro, cyano, cyanoalkyl, amino, alkylamino,dialkylamino, —(CH₂)_(k)-Z⁵R⁵⁰, —(CH₂)_(k)—COR⁵¹ and —(CH₂)_(k)—COOR⁵¹,Z⁴ and Z⁵ representing a bond, —O—, —NR⁵²— or —S—,or R⁴⁶ and R⁴⁷ taken together form with the nitrogen atom a non aromaticheterocycle with 4 to 8 members, the elements of the chain being chosenfrom a group comprising —CH(R⁵³)—, —NR⁵⁴—, —O—, —S— and —CO—, saidheterocycle being able to be for example an azetidine, a piperazine, ahomopiperazine, a 3,5-dioxopiperazine, a piperidine, a pyrrolidine, amorpholine or a thiomorpholine,R⁵⁰ and R⁵², representing, independently each time that they occur, ahydrogen atom or an alkyl, alkenyl, alkynyl, allenyl, allenylalkyl orcyanoalkyl radical,R⁵¹ representing, independently each time that they occur, a hydrogenatom, a linear or branched alkyl radical containing 1 to 8 carbon atoms,an alkenyl, alkynyl, allenyl, allenylalkyl, cyanoalkyl or NR⁵⁸R⁵⁹radical,R⁵⁸ and R⁵⁹ representing, independently, a hydrogen atom or an alkyl,alkenyl, alkynyl, allenyl, allenylalkyl or cyanoalkyl radical,R⁵³ and R⁵⁴ representing, independently, a hydrogen atom or a—(CH₂)_(k)-Z⁷R⁶⁰ or —(CH₂)_(k)—COR⁶¹ radical,Z⁷ representing a bond, —O—, —NR⁶²— or —S—,R⁶⁰ and R⁶² representing, independently, a hydrogen atom or an alkyl,alkenyl, allenyl, allenylalkyl, alkynyl, cyanoalkyl, aryl, aralkyl,arylcarbonyl, aralkylcarbonyl, pyridinyl, pyridinylalkyl orpyridinylcarbonyl radical, the aryl or pyridinyl group of the aryl,aralkyl, arylcarbonyl, aralkylcarbonyl, pyridinyl, pyridinylalkyl orpyridinylcarbonyl radicals being optionally substituted by one or moresubstituents chosen from the group constituted by the alkyl, halogen,nitro, alkoxy, cyano, cyanoalkyl, —(CH₂)_(k)-Z⁸R⁶³ and —(CH₂)_(k)—COR⁶⁴radicals,R⁶¹ representing a hydrogen atom, an alkyl, allenyl, allenylalkyl,alkenyl, alkynyl, cyanoalkyl, alkoxy or NR⁶⁵R⁶⁶ radical,R⁶⁵ and R⁶⁶ representing, independently, a hydrogen atom or an alkyl,allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radical,Z⁸ representing a bond, —O—, —NR⁶⁷— or —S—,R⁶³ and R⁶⁷ representing, independently, a hydrogen atom, an alkyl,allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radical,R⁶⁴ representing a hydrogen atom, an alkyl, allenylalkyl, alkenyl,alkenyl, alkynyl, cyanoalkyl, alkoxy or NR⁶⁸R⁶⁹ radical,R⁶⁸ and R⁶⁹ representing, independently, a hydrogen atom or an alkyl,allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radical,and R⁴⁸ represents a hydrogen atom or an alkyl, alkynyl or cyanoalkylradical;g and p, each time that they occur, being independently integers from 1to 6, and k and n, each time that they occur, being independentlyintegers from 0 to 6.

As regards the compounds of general formula (I) (or their salts) moreespecially intended to have an inhibitory activity on MAO's and theROS's, the said compounds compounds having at least one of the followingcharacteristics will generally be preferred:

-   -   the compound corresponds to general sub-formula (I), or (I), in        which X represents S, the compounds corresponds to general        formula (I), in which Y represents O or the compound corresponds        to general sub-formula (I)₄;    -   A represents the radical        -   either the        -   radical in which R⁴, R⁵, R⁶, R⁷ and R⁸ represent,            independently, a hydrogen atom, or an alkyl or alkoxy            radical,        -   R⁹ represents a hydrogen atom,        -   and W doesn't exist, or represents a bond, —O— or —S—,        -   or the        -   radical in which Q represents OH, two of the R¹⁹, R²⁰ and            R²¹ radicals' represent the radicals chosen independently            from the alkyl, alkoxy, alkylthio, amino, alkylamino or            dialkylamino radicals and the third represents a radical            chosen from a hydrogen atom and the alkyl, alkoxy,            alkylthio, amino, alkylamino or dialkylamino radicals, or in            which Q represents a phenyl radical substituted by an OH            radical and a radical or radicals chosen independently from            a halogen atom and an OH, alkyl, alkoxy or —NR¹⁰R¹¹ radical            in which R¹⁰ and R¹¹ represent independently a hydrogen atom            or an alkyl radical,        -   or also the        -   radical        -   or finally the        -   radical in which T represents —CH₂— and R³³ represents a            hydrogen atom, an aminoalkyl, alkylaminoalkyl or            dialkylaminoalkyl radical;    -   B represents H;    -   n represents 0 or 1;    -   R¹ and R² both represent H;    -   Ω represents        -   preferably: an NR⁴⁶R⁴⁷ radical such that NR⁴⁶R⁴⁷ represents            the N-piperazinyl radical or the N-piperazinyl radical            optionally N-substituted by an alkyl radical or in which one            of R⁴⁶ and R⁴⁷ represents H or a hydroxyalkyl, alkynyl or            cyanoalkyl radical and the other represents H or an alkyl            radical.        -   or the OR⁴⁸ radical in which R⁴⁸ represents a hydrogen atom            or an alkyl, alkynyl or cyanoalkyl radical.

As regards the compounds of general formula (I) (or their salts) moreespecially intended to have an inhibitory activity on MAO's and theROS's, the said compounds having at least one of the followingcharacteristics will be quite particularly preferred:

-   -   the compound corresponds to general sub-formula (I), or (I), in        which X represents S or the compound corresponds to general        formula (I), in which Y represents O;    -   A represents the        -   radical in which Q represents OH, two of the R¹⁹, R²⁰ and            R²¹ radicals represent an alkyl radical and the third            represents H,        -   or in which Q represents a phenyl radical substituted by an            OH radical and one or more radicals chosen independently            from the alkyl radicals;    -   B represents H;    -   n represents 0 or 1;    -   R¹ and R² both represent H;    -   Ω represents:        -   preferably: an NR⁴⁶R⁴⁷ radical such that NR⁴⁶R⁴⁷ represents            an N-piperazinyl radical or in which one of R⁴⁶ and R⁴⁷            represents H or a hydroxyalkyl, alkynyl or cyanoalkyl            radical and the other represents H or an alkyl radical,        -   or the OH radical.

In particular, the compounds of Examples 1 to 30, 210, 291, 316, 319 to323, 329 to 336 and 346 to 349 (sometimes described in the form ofsalts) or their pharmaceutically acceptable salts are preferred when aninhibitory activity on MAO's and/or the ROS's is sought in the firstplace. Even more preferentially, the compounds of Examples 1, 3, 6, 22,24, 26 to 29, 323 and 332 (sometimes described in the form of salts), ortheir pharmaceutically acceptable salts, are preferred when aninhibitory activity on MAO's and/or the ROS's is sought in the firstplace.

According to another variant of the invention, the compounds of generalformula (I) or their pharmaceutically acceptable salts are moreespecially intended to have an modulating activity on the sodiumchannels and they are then preferably such that they correspond togeneral sub-formulae (I), and (I)₂ and that:

A represents

either a

radical in which Q represents H, —OR²², SR²² or a phenyl radicaloptionally substituted by one or more of the substituents chosenindependently from a halogen atom, an alkyl or alkoxy radical, and agroup of two substituents together representing a methylenedioxy orethylenedioxy radical, or Q represents a —COPh, —OPh, —SPh, —SO₂Ph or—CH₂Ph radical, said —COPh, —OPh, —SPh, —SO₂Ph or —CH₂Ph radical beingoptionally substituted on its aromatic part by one or more of thesubstituents chosen independently from an alkyl or alkoxy radical and ahalogen atom,R²² representing a hydrogen atom or an alkyl radical,and R¹⁹, R²⁰ and R²¹ represent, independently, a hydrogen, a halogen,the OH group or an alkyl, alkoxy, cyano, nitro, cycloalkyl, —SO₂NHR⁴⁹,—CONHR⁵⁵, —S(O)_(q)R56, —NH(CO)R⁵⁷, —CF₃, —OCF₃ or NR²⁷R²⁸ radical,R²⁷ and R²⁸ representing, independently, a hydrogen atom or an alkylradical or R²⁷ and R²⁸ forming together with the nitrogen atom whichcarries them a heterocycle with 5 to 6 members chosen from —CH₂—, —NH—and —O—,R⁴⁹ and R⁵⁵ representing, independently each time that they occur, ahydrogen atom or an alkyl or alkylcarbonyl radical,q representing an integer from 0 to 2,R⁵⁶ and R⁵⁷ representing, independently each time that they occur, ahydrogen atom or an alkyl or alkoxy radical,or a

radical in which R⁴, R⁵, R⁶, R⁷ and R⁸ represent, independently, ahydrogen atom, a halogen, the OH group or an alkyl, alkoxy or NR¹⁰R¹¹radical,R¹⁰ and R¹¹ representing, independently, a hydrogen atom or an alkylradical, or R¹⁰ and R¹¹ forming together with the nitrogen atom anoptionally substituted heterocycle comprising 4 to 7 members and 1 to 3heteroatoms including the nitrogen atom already present, the additionalheteroatoms being chosen independently from the group constituted by theO, N and S atoms, said heterocycle being able to be for exampleazetidine, pyrrolidine, piperidine, piperazine, morpholine orthiomorpholine,R⁹ represents a hydrogen atom or an alkyl radical,and W does not exist, or represents a bond, or —O—, —S— or —NR¹⁸—, inwhich R¹⁸ represents a hydrogen atom or an alkyl radical;or a

radical in which R³² represents a hydrogen atom or an alkyl radical,and T represents a —(CH₂)_(m)— radical with m=1 or 2,or also A represents an alkyl, cycloalkyl or cycloalkylalkyl radical;B represents a hydrogen atom, a linear or branched alkyl radicalcontaining 1 to 6 carbon atoms or a carbocyclic aryl radical optionallysubstituted 1 to 3 times by the radicals chosen from the group composedof a halogen atom, an alkyl or alkoxy radical, a hydroxy, cyano or nitroradical, an amino, alkylamino or dialkylamino radical and a carbocyclicaryl radical;X represents NR³⁸ or S,R³⁸ representing a hydrogen atom or an alkyl, aralkyl, alkylcarbonyl oraralkylcarbonyl radical,R¹ and R² represent, independently, a hydrogen atom, an alkyl,cycloalkyl, cycloalkylalkyl, alkoxyalkyl, aminoalkyl, —(CH₂)_(g)NH—CO—R⁷⁰ radical or an aralkyl or heteroarylalkyl radical optionallysubstituted on the aryl or heteroaryl group by one or more groups chosenfrom the group composed of a halogen atom, an alkyl or alkoxy radical, ahydroxy, cyano or nitro radical and an amino, alkylamino or dialkylaminoradical,R⁷⁰ representing, independently each time that it occurs, an alkyl oralkoxy radical;R¹ and R² taken together can optionally form with the carbon atom whichcarries them a carbocycle with 3 to 7 members;Ω represents OH or an NR⁴⁶R⁴⁷ radical, in which:R⁴⁶ and R⁴⁷ represent, independently, a hydrogen atom or an alkyl,cycloalkyl or cycloalkylalkyl, —CO—NH—R⁵¹, —CO—O—R⁵¹ or —SO₂—R⁷² radicalor one of the heteroaryl, aralkyl, aryloxyalkyl or arylimino radicalsoptionally substituted on the heteroaryl or aryl group by one or moregroups chosen from the group composed of a halogen atom, a linear orbranched alkyl or alkoxy radical containing 1 to 6 carbon atoms, ahydroxy, cyano or nitro radical, an amino, alkylamino or dialkylaminoradical,R⁵¹ representing a hydrogen atom, one of the cycloalkyl orcycloalkylalkyl radicals in which the cycloalkyl radical contains 3 to 7carbon atoms, a linear or branched alkyl radical containing 1 to 8carbon atoms, an alkoxyalkyl radical or also an aryl or aralkyl radical,said aryl or aralkyl radical being able to be substituted by one or moreof the substituents chosen independently from a halogen atom and analkyl or alkoxy radical, and R⁷² representing an alkyl radical, or oneof the phenyl or aralkyl radicals optionally substituted on the aromaticring by one or more of the radicals chosen from a halogen atom, an alkylor alkoxy radical;g represents an integer from 1 to 6; and finallyn represents an integer from 0 to 6.

More preferentially, the compounds of general formula (I) (or theirpharmaceutically acceptable salts) intended to have a modulatingactivity on the sodium channels corresponding to general sub-formulae(I), and (I)₂ and will be such that:A represents the

radical in which Q represents H, —OR²², —SR²², or a phenyl radicaloptionally substituted by one or more of the substituents chosenindependently from a halogen atom and an alkyl or alkoxy radical, oralso Q represents a —COPh, —OPh, —SPh, —SO₂Ph or —CH₂Ph radical, said—COPh, —OPh, —SPh, —SO₂Ph or —CH₂Ph radical being optionally substitutedon its aromatic part by one or more of the substituents chosen from analkyl or alkoxy radical and a halogen atom,R²² representing a hydrogen atom or an alkyl radical,and R¹⁹, R²⁰ and R²¹ represent, independently, a hydrogen, a halogen,the OH group or an alkyl, alkoxy, cyano, nitro, cycloalkyl, —SO₂NHR⁴⁹,—CONHR⁵⁵, —S(O)_(q)R⁵⁶—NH(CO)R⁵⁷, —OCF₃ or NR²⁷R²⁸ radical,R²⁷ and R²⁸ representing, independently, a hydrogen atom or an alkylradical or R²⁷ and R²⁸ forming together with the nitrogen atom whichcarries them a heterocycle with 5 to 6 members chosen from —CH₂—, —NH—and —O—,R⁴⁹ and R⁵⁵ representing, independently each time that they occur, ahydrogen atom or an alkyl or alkylcarbonyl radical,q representing an integer from 0 to 2,R⁵⁶ and R⁵⁷ representing, independently each time that they occur, ahydrogen atom or an alkyl or alkoxy radical,or also A represents an alkyl, cycloalkyl or cycloalkylalkyl radical,B represents a hydrogen atom, a linear or branched alkyl radicalcontaining 1 to 6 carbon atoms or a carbocyclic aryl radical optionallysubstituted 1 to 3 times by the radicals chosen from the group composedof a halogen atom, an alkyl or alkoxy radical, a hydroxy, cyano or nitroradical, an amino, alkylamino or dialkylamino radical and a carbocyclicaryl radical;X represents NR³⁸ or S,R³⁸ representing a hydrogen atom or an alkyl, aralkyl, alkylcarbonyl oraralkylcarbonyl radical,R¹ and R² represent, independently, a hydrogen atom, an alkyl,cycloalkyl, cycloalkylalkyl, alkoxyalkyl, aminoalkyl,—(CH₂)_(g)—NH—CO—R⁷⁰ radical or an aralkyl or heteroarylalkyl radicaloptionally substituted on the aryl or heteroaryl group by one or moregroups chosen from the group composed of a halogen atom, an alkyl oralkoxy radical, a hydroxy, cyano or nitro radical and an amino,alkylamino or dialkylamino radical,R⁷⁰ representing, independently each time that it occurs, an alkyl oralkoxy radical;R¹ and R² taken together can optionally form with the carbon atom whichcarries them a carbocycle with 3 to 7 members;Ω represents the NR⁴⁶R⁴⁷ radical, in which:R⁴⁶ and R⁴⁷ represent, independently, a hydrogen atom or an alkyl,cycloalkyl or cycloalkylalkyl, —CO—NH—R⁵¹, —CO—O—R⁵¹ or —SO₂—R⁷² radicalor one of the heteroaryl, aralkyl, aryloxyalkyl or arylimino radicalsoptionally substituted on the heteroaryl or aryl group by one or moregroups chosen from the group composed of a halogen atom, a linear orbranched alkyl or alkoxy radical containing 1 to 6 carbon atoms, ahydroxy, cyano or nitro radical, an amino, alkylamino or dialkylaminoradical,R⁵¹ representing a hydrogen atom, one of the cycloalkyl orcycloalkylalkyl radicals in which the cycloalkyl radical contains 3 to 7carbon atoms, a linear or branched alkyl radical containing 1 to 8carbon atoms, an alkoxyalkyl radical or also an aryl or aralkyl radical,said aryl or aralkyl radical being able to be substituted by one or moreof the substituents chosen independently from a halogen atom and analkyl or alkoxy radical, and R⁷² representing an alkyl radical, or oneof the phenyl or aralkyl radicals optionally substituted on the aromaticring by one or more of the radicals chosen from a halogen atom, an alkylor alkoxy radical and finally;n represents an integer from 0 to 6.

As regards the compounds of general formula (I) (or their salts) moreespecially intended to have a modulating activity on the sodiumchannels, said compounds of general sub-formula (I), or (I)₂ willgenerally be preferred having at least one of the followingcharacteristics:

-   -   A represents:        -   the        -   radical in which Q represents a hydrogen atom, a halogen            atom, the OH group, an alkoxy, alkylthio or phenyl radical            optionally substituted by one or more radicals chosen from a            halogen atom and an alkoxy radical,        -   and R¹⁹, R²⁰ and R²¹ represent, independently, a hydrogen            atom, a halogen atom, the OH group or an alkyl, alkoxy,            cyano, nitro, cycloalkyl, —SO₂NHR⁴⁹, —CONHR⁵⁵, —S(O)_(q)R⁵⁶,            —NH(CO)R⁵⁷, —CF₃, —OCF₃ or NR²⁷R²⁸ radical,        -   R²⁷ and R²⁸ representing, independently, a hydrogen atom or            an alkyl radical or R²⁷ and R²⁹ forming together with the            nitrogen atom which carries them a heterocycle with 5 to 6            members chosen from —CH₂—, —NH— and —O—,        -   R⁴⁹ and R⁵⁵ representing, independently each time that they            occur, a hydrogen atom or an alkyl or alkylcarbonyl radical,        -   q representing an integer from 0 to 2,        -   R⁵⁶ and R⁵⁷ representing, independently each time that they            occur, a hydrogen atom or an alkyl or alkoxy radical;        -   or an alkyl, cycloalkyl or cycloalkylalkyl radical;    -   B represents H, alkyl, or phenyl;    -   n represents 0 or 1;    -   R¹ and R² are such that:        -   R¹ and R² represent independently H, an alkyl, cycloalkyl            radical and in particular cyclohexyl, cycloalkylalkyl, or            also an aralkyl or heteroarylalkyl radical optionally            substituted on the aryl or heteroaryl group by one or more            groups chosen from the group comprising a halogen atom, an            alkyl or alkoxy radical; in particular, R¹ represents a            linear or branched alkyl radical containing 2 to 6 carbon            atoms, and preferably 4 to 6 carbon atoms, the cyclohexyl            radical or the indolylmethyl radical optionally substituted            and R² represents H;        -   or R¹ and R² taken together with the carbon atom which            carries them a carbocycle with 3 to 7 members;    -   Ω represents an OH radical or preferably an NR⁴⁶R⁴⁷ radical in        which R⁴⁶ represents H, an alkyl radical and in particular        isopropyl, n-pentyl or n-hexyl, a cycloalkylalkyl radical, a        cycloalkyl radical and in particular cyclobutyl, cyclopentyl or        cyclohexyl, an alkylcarbonyl radical, an alkoxycarbonyl radical,        a (cycloalkyl)oxycarbonyl radical, a cycloalkylalkoxycarbonyl        radical, an alkylaminocarbonyl radical or also a benzyl radical        optionally substituted by an alkoxy radical, and R⁴⁷ represents        H;    -   X represents S or preferably the NR³⁸ radical in which R³⁸        represents a hydrogen atom or an alkyl, aralkyl, alkylcarbonyl        or aralkylcarbonyl radical.

As regards the compounds of general formula (I) (or their salts) moreparticularly intended to have a modulatory activity on the sodiumchannels, said compounds of general sub-formula (I), or (I)₂ comprisingat least one of the following characteristics will be even moreparticularly preferred:

-   -   A represents:        -   the        -   radical in which Q represents a hydrogen atom, a halogen            atom or an alkoxy, alkylthio or phenyl radical optionally            substituted by one or more radicals chosen from a halogen            atom and an alkoxy radical,        -   and R¹⁹, R²⁰ and R²¹ represent, independently, a hydrogen            atom, a halogen atom or an alkyl, alkoxy, cyano, cycloalkyl,            —CF₃ or NR²⁷R²⁸ radical,        -   R²⁷ and R²⁸ representing, independently, a hydrogen atom or            an alkyl radical or R²⁷ and R²⁸ forming together with the            nitrogen atom which carries them a heterocycle with 5 to 6            members chosen from —CH₂— and —NH—;        -   or a cycloalkyl radical;    -   B represents H;    -   n represents 0 or 1;    -   R¹ represents H, an alkyl, cycloalkyl and in particular a        cyclohexyl radical, and R² represents H;    -   Ω represents an NR⁴⁶R⁴⁷ radical in which R⁴⁶ represents a        cycloalkylalkyl radical, a cycloalkyl radical and in particular        cyclobutyl or cyclohexyl, an alkoxycarbonyl radical, a        (cycloalkyl)oxycarbonyl radical, a cycloalkylalkoxycarbonyl        radical or also a benzyl radical optionally substituted by an        alkoxy radical, and R⁴⁷ represents H;    -   X represents the NH radical.

Furthermore, still for the compounds more particularly intended to havea modulatory activity on sodium channels, when n represents 1, R¹ and R²will preferably represent hydrogen atoms.

In particular, the compounds of Examples 1, 3, 6, 7, 9 to 11, 13, 15 to17, 20, 24, 26, 28 to 318, 321, 324 to 330 and 337 to 345 (sometimesdescribed in the form of salts), or their pharmaceutically acceptablesalts, are preferred when a modulating activity on the sodium channelsis sought in the first place.

More preferentially, the compounds of Examples 1, 6, 7, 11, 13, 15, 17,20, 24, 31 to 38, 42, 43, 46 to 48, 53, 56, 57, 59 to 61, 64 to 80, 82to 88, 9′ to 95, 97, 105, 106, 108, 110, 113, 117, 118, 121 to 123, 125,128, 130 to 139, 142 to 145, 149, 151, 152, 154, 162 to 166, 168 to 178,181, 183 to 186, 188, 190 to 196, 198 to 206, 208 to 210, 212 to 218,220 to 231, 233 to 250, 252 to 259, 261 to 281, 283 to 288, 293 to 313,324 and 338 to 340 (sometimes described in the form of salts), or theirpharmaceutically acceptable salts, are preferred when a modulatingactivity on the sodium channels is sought in the first place.

According to a more particular variant of the invention, the compoundsof the invention of general formula (I) as defined previously in which:

Het is such that the compounds of general formula (I) correspond to oneof the general sub-formulae (I), and (I), in which X represents NH or Sor general sub-formula (I)₃ in which Y represents O;

A represents a

radical in which Q represents OH, two of the R¹⁹, R²⁰ and R²¹ radicalsrepresent an alkyl radical and the third represents a hydrogen atom,or in which Q represents a phenyl radical substituted by an OH radicaland one or more radicals chosen independently from alkyl radicals;B represents a hydrogen atom;n represents 0 or 1;R¹ and R² both represent a hydrogen atom;and Ω represents an NR⁴⁶R⁴⁷ radical in which R⁴⁶ represents a hydrogenatom or an alkyl, alkynyl, hydroxyalkyl or cyanoalkyl radical and R⁴⁷represents a hydrogen atom or an alkyl radical or also R⁴⁶ and R⁴⁷ formtogether with the nitrogen atom which carries them a non-aromaticheterocycle with 5 to 7 members, the additional members being chosenfrom —CH₂— and —NH—;can be used to prepare a medicament intended both to inhibit MAO's andlipidic peroxidation and to modulate the sodium channels.

More preferentially, the compounds of general formula (I) which can beused to prepare a medicament intended both to inhibit MAO's and lipidicperoxidation and to modulate the sodium channels will be such that:

Het is such that the compounds of general formula (I) correspond togeneral sub-formula (I), in which X represents S or to generalsub-formula (I)₃ in which Y represents O;

A represents a

radical in which Q represents OH, two of the radicals R¹⁹, R²⁰ and R²¹represent an alkyl radical and the third represents a hydrogen atom;B represents a hydrogen atom;n represents 0 or 1;R¹ and R² both represent a hydrogen atom;and Ω represents an NR⁴⁶R⁴⁷ radical in which R⁴⁶ represents a hydrogenatom or an alkyl, hydroxyalkyl or cyanoalkyl radical and R⁴⁷ representsa hydrogen atom or an alkyl radical or also R⁴⁶ and R⁴⁷ form togetherwith the nitrogen atom which carries them an N-piperazinyl radical.

Still for the compounds of general formula (I) which can be used toprepare a medicament intended both to inhibit the MAO's and lipidicperoxidation and to modulate the sodium channels, n will preferablyrepresent 0 when Het is such that the compounds of general formula (I)correspond to general sub-formula (I), in which X represents S andpreferably 1 when Het is such that the compounds of general formula (I)correspond to general sub-formula (I)₃ in which Y represents O.

In particular, the compounds of Examples 1, 3, 6, 24, 26, 28 and 29(sometimes described in the form of salts) or their pharmaceuticallyacceptable salts will be preferred if one wishes to prepare a medicamentintended both to inhibit MAO's and lipidic peroxidation and to modulatethe sodium channels.

The invention also offers, as medicaments, the compounds of generalformula (II)

in racemic, enantiomeric form or any combinations of these forms, inwhich Het is a heterocycle with 5 members comprising 2 heteroatoms andsuch that general formula (II) correspond exclusively to one of thefollowing sub-formulae:

in whichA representseither a

radical in which R³ represents a hydrogen atom, the OH group or analkoxy or alkyl radical,or a

radical in which R⁴, R⁵, R⁶, R⁷ and R⁸ represent, independently, ahydrogen atom, a halogen, the OH group or an alkyl, alkoxy, cyano, nitroor NR¹⁰R¹¹ radical,R¹⁰ and R¹¹ representing, independently, a hydrogen atom, an alkylradical or a —COR¹² group, or R¹⁰ and R¹¹ forming together with thenitrogen atom an optionally substituted heterocycle containing 4 to 7members and 1 to 3 heteroatoms including the nitrogen atom alreadypresent, the additional heteroatoms being chosen independently from thegroup constituted by the O, N and S atoms,R¹² representing a hydrogen atom or an alkyl, alkoxy or NR¹³R¹⁴ radical,R¹³ and R¹⁴ representing, independently, a hydrogen atom or an alkylradical, or R¹³ and R¹⁴ forming together with the nitrogen atom anoptionally substituted heterocycle with 4 to 7 members and 1 to 3heteroatoms including the nitrogen atom already present, the additionalheteroatoms being chosen independently from the group constituted by theO, N and S atoms,R⁹ represents a hydrogen atom, an alkyl radical or a —COR¹⁵ group,R¹⁵ representing a hydrogen atom or an alkyl, alkoxy or NR¹⁶R¹⁷ radical,R¹⁶ and R¹⁷ representing, independently, a hydrogen atom or an alkylradical, or R¹⁶ and R¹⁷ forming together with the nitrogen atom anoptionally substituted heteroatom with 4 to 7 members and 1 to 3heteroatoms including the nitrogen atom already present, the additionalheteroatoms being chosen independently from the group constituted by theO, N and S atoms,and W doesn't exist, or represents a bond, or —O—, —S— or —NR¹⁸—, inwhich R¹⁸ represents a hydrogen atom or an alkyl radical;or a

radical in which Q represents H, —OR²², —SR²², —NR²³R²⁴, a phenylradical optionally substituted by one or more of the substituents chosenindependently from a halogen atom, an OH, cyano, nitro, alkyl, alkoxy or—NR¹⁰R¹¹ radical and a group with two substituents together representinga methylenedioxy or ethylenedioxy radical, or also Q represents a —COPh,—SO₂Ph or —CH₂Ph radical, said —COPh, —SO₂Ph or —CH₂Ph radical beingoptionally substituted on its aromatic part by one or more of thesubstituents chosen independently from an alkyl or alkoxy radical and ahalogen atom,R¹⁰ and R¹¹ representing, independently, a hydrogen atom, an alkylradical or a —OR¹² group, or R¹⁰ and R¹¹ forming together with thenitrogen atom an optionally substituted heterocycle containing 4 to 7members and 1 to 3 heteroatoms including the nitrogen atom alreadypresent, the additional heteroatoms being chosen independently from thegroup constituted by the O, N and S atoms,R¹² representing a hydrogen atom, an alkyl or alkoxy or NR¹³R¹⁴ radical,R¹³ and R¹⁴ representing, independently, a hydrogen atom or an alkylradical, or R¹³ and R¹⁴ forming together with the nitrogen atom anoptionally substituted heterocycle with 4 to 7 members and 1 to 3heteroatoms including the nitrogen atom already present, the additionalheteroatoms being chosen independently from the group constituted by theO, N and S atoms,R²² representing a hydrogen atom, an alkyl radical or an aryl radicaloptionally substituted by one or more substituents chosen from thealkyl, OH, halogen, nitro and alkoxy radicals,R²³ and R²⁴ representing, independently, a hydrogen atom, an alkylradical or a —CO—R²⁵ radical,R²⁵ representing an alkyl radical,and R¹⁹, R²⁰ and R²¹ represent, independently, a hydrogen, a halogen,the OH or SR²⁶ group, or an alkyl, cycloalkyl, alkenyl, alkoxy, cyano,nitro, —SO₂NHR⁴⁹, —CONHR⁵⁵, —S(O)_(q)R⁵⁶, —NH(CO)R⁵⁷, —CF, —OCF₃ orNR²⁷R²⁸ radical,R²⁶ representing a hydrogen atom or an alkyl radical,R²⁷ and R²⁸ representing, independently, a hydrogen atom, an alkylradical or a —COR²⁹ group, or R²⁷ and R²⁸ forming together with thenitrogen atom an optionally substituted heterocycle containing 4 to 7members and 1 to 3 heteroatoms including the nitrogen atom alreadypresent, the additional heteroatoms being chosen independently from thegroup constituted by the O, N and S atoms,R⁴⁹ and R⁵⁵ representing, independently each time that they occur, ahydrogen atom or an alkyl or alkylcarbonyl radical,q representing an integer from 0 to 2,R⁵⁶ and R⁵⁷ representing, independently each time that they occur, ahydrogen atom or an alkyl or alkoxy radical,R²⁹ representing a hydrogen atom, an alkyl, alkoxy or —NR³⁰R³¹ radical,R³⁰ and R³¹ representing, independently, a hydrogen atom or an alkylradical, or R³⁰ and R³¹ forming together with the nitrogen atom anoptionally substituted heterocycle containing 4 to 7 members and 1 to 3heteroatoms including the nitrogen atom already present, the additionalheteroatoms being chosen independently from the group constituted by theO, N and S atoms,or a

radical in which R³² represents a hydrogen atom or an alkyl radical,and T represents a —(CH₂)_(m)— radical with m=1 or 2,or finally a

radical in which R³³ represents a hydrogen atom or an alkyl, -Σ-NR³⁴R³⁵or -Σ-CHR³⁶R³⁷ radical,Σ representing a linear or branched alkylene radical containing 1 to 6carbon atoms,R³⁴ and R³⁵ representing, independently, a hydrogen atom or an alkylradical,R³⁶ and R³⁷ representing, independently, a hydrogen atom or acarbocyclic or heterocyclic aryl radical optionally substituted by oneor more substituents chosen from the alkyl, OH, halogen, nitro, alkoxyor NR¹⁰R¹¹ radicals,R¹⁰ and R¹¹ representing, independently, a hydrogen atom, an alkylradical or a —COR¹² group, or R¹⁰ and R¹¹ forming together with thenitrogen atom an optionally substituted heterocycle containing 4 to 7members and 1 to 3 heteroatoms including the nitrogen atom alreadypresent, the additional heteroatoms being chosen independently from thegroup constituted by the O, N and S atoms,R¹² representing a hydrogen atom or an alkyl, alkoxy or NR¹³R¹⁴ radical,R¹³ and R¹⁴ representing, independently, a hydrogen atom or an alkylradical, or R¹³ and R¹⁴ forming together with the nitrogen atom anoptionally substituted heterocycle with 4 to 7 members and 1 to 3heteroatoms including the nitrogen atom already present, the additionalheteroatoms being chosen independently from the group constituted by theO, N and S atoms,and T represents a —(CH₂)_(m)— radical with m=1 or 2,or also A represents an alkyl, cycloalkyl or cycloalkylalkyl radical;X represents S or NR³⁸,R³⁸ representing a hydrogen atom or an alkyl, cyanoalkyl, aralkyl,alkylcarbonyl or aralkylcarbonyl radical,Y represents O or S;R¹ represents a hydrogen atom, an alkyl, aminoalkyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, trifluoromethylalkyl, alkenyl, allenyl,allenylalkyl, alkynyl, cyanoalkyl, —(CH₂)_(g)-Z¹R³⁹, —(CH₂)_(g)—COR⁴⁰,—(CH₂)_(g)—NHCOR⁷⁰, aryl, aralkyl, arylcarbonyl, heteroarylalkyl oraralkylcarbonyl radical, the aryl group of the aryl, aralkyl,arylcarbonyl, heteroarylalkyl or aralkylcarbonyl radicals being itselfoptionally substituted by one or more substituents chosen from the groupconstituted by the alkyl, halogen, alkoxy, nitro, cyano, cyanoalkyl,amino, alkylamino, dialkylamino, —(CH₂)_(k)-Z²R³⁹ or —(CH₂)_(k)—COR⁴⁰radicals,Z¹ and Z² representing a bond, —O—, —NR⁴¹— or —S—,R³⁹ and R⁴¹ representing, independently each time that they occur, ahydrogen atom or an alkyl, alkenyl, alkynyl or cyanoalkyl radical,R⁴⁰ representing, independently each time that it occurs, a hydrogenatom or an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl, cyanoalkyl,alkoxy or NR⁴²R⁴³ radical,R⁴² and R⁴³ representing, independently each time that they occur, ahydrogen atom or an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl orcyanoalkyl radical,and R² represents a hydrogen atom, an alkyl, aminoalkyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, trifluoromethylalkyl or —(CH₂)_(g)—NHCOR⁷¹radical, or also one of the aralkyl or heteroarylalkyl radicalsoptionally substituted on the aryl or heteroaryl group by one or more ofthe groups chosen independently from the group composed of a halogenatom and an alkyl, alkoxy, hydroxy, cyano, nitro, amino, alkylamino ordialkylamino radical,R⁷⁰ and R⁷¹ representing independently an alkyl or alkoxy radical;or R¹ and R², taken together with the carbon atom which carries them,form a carbocycle with 3 to 7 members;B represents a hydrogen atom, an alkyl radical, a —(CH₂)_(g)-Z³R⁴⁴radical or a carbocyclic aryl radical optionally substituted 1 to 3times by the radicals chosen from the group composed of a halogen atom,a linear or branched alkyl or alkoxy radical containing 1 to 6 carbonatoms, a hydroxy, cyano or nitro radical, an amino, alkylamino ordialkylamino radical and a carbocyclic aryl radical,Z³ representing a bond, —O—, —NR⁴⁵— or —S—,R⁴⁴ and R⁴⁵ representing, independently, a hydrogen atom or an alkyl,alkenyl, alkynyl, allenyl, allenylalkyl or cyanoalkyl radical;Ω represents one of the NR⁴⁶R⁴⁷ or OR⁴⁸ radicals, in which:R⁴⁶ and R⁴⁷ represent, independently, a hydrogen atom or an alkyl,cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, allenyl, allenylalkyl,cyanoalkyl, —(CH₂)_(g)-Z⁴R⁵⁰, —(CH₂)_(k)—COR⁵¹, —(CH₂)_(k)—COOR⁵¹,—(CH₂)_(k)—CONHR⁵¹ or —SO₂R⁵¹ radical, or also a radical chosen from thearyl, aralkyl, aryloxyalkyl, arylcarbonyl, arylimino, aralkylcarbonyl,heteroaryl and in particular pyridinyl, pyridinylalkyl orpyridinylcarbonyl radicals, the aryl or heteroaryl group of said aryl,aralkyl, aryloxyalkyl, arylcarbonyl, arylimino, aralkylcarbonyl,heteroaryl, pyridinylalkyl or pyridinylcarbonyl radicals beingoptionally substituted by one or more of the substituents chosenindependently from halogen, alkyl, alkoxy, hydroxy, nitro, cyano,cyanoalkyl, amino, alkylamino, dialkylamino, —(CH₂)_(k)-Z⁵R⁵⁰,—(CH₂)_(k)—COR⁵¹ and —(CH₂)_(k)—COOR⁵¹,Z⁴ and Z⁵ representing a bond, —O—, —NR⁵²— or —S—,or R⁴⁶ and R⁴⁷ taken together form with the nitrogen atom a non aromaticheterocycle with 4 to 8 members, the elements of the chain being chosenfrom a group composed of —CH(R⁵³)—, —NR⁵⁴—, —O—, —S— and —CO—,R⁵⁰ and R⁵², representing, independently each time that they occur, ahydrogen atom or an alkyl, alkenyl, alkynyl, allenyl, allenylalkyl orcyanoalkyl radical,R⁵¹ representing, independently each time that they occur, a hydrogenatom, one of the cycloalkyl or cycloalkylalkyl radicals in which thecycloalkyl radical contains 3 to 7 carbon atoms, a linear or branchedalkyl radical containing 1 to 8 carbon atoms, an alkenyl, alkynyl,allenyl, allenylalkyl, cyanoalkyl, alkoxyalkyl or NR⁵⁸R⁵⁹ radical, oralso an aryl or aralkyl radical, said aryl or aralkyl radical being ableto be substituted by one or more of the substituents chosenindependently from a halogen atom and an alkyl or alkoxy radical,R⁵⁸ and R⁵⁹ representing, independently, a hydrogen atom or an alkyl,alkenyl, alkynyl, allenyl, allenylalkyl or cyanoalkyl radical,R⁵³ and R⁵⁴ representing, independently, a hydrogen atom or a—(CH₂)_(k)-Z⁷R⁶⁰ or —(CH₂)_(k)—COR⁶¹ radical,Z⁷ representing a bond, —O—, —NR⁶²— or —S—,R⁶⁰ and R⁶² representing, independently, a hydrogen atom or an alkyl,alkenyl, allenyl, allenylalkyl, alkynyl, cyanoalkyl, aryl, aralkyl,arylcarbonyl, aralkylcarbonyl, pyridinyl, pyridinylalkyl orpyridinylcarbonyl radical, the aryl or pyridinyl group of the aryl,aralkyl, arylcarbonyl, aralkylcarbonyl, pyridinyl, pyridinylalkyl orpyridinylcarbonyl radicals being optionally substituted by one or moresubstituents chosen from the group constituted by the alkyl, halogen,nitro, alkoxy, cyano, cyanoalkyl, —(CH₂)_(k)-Z⁸R⁶³ and —(CH₂)_(k)—COR⁶⁴radicals,R⁶¹ representing a hydrogen atom, an alkyl, allenyl, allenylalkyl,alkenyl, alkynyl, cyanoalkyl, alkoxy or NR⁶⁵R⁶⁶ radical,R⁶⁵ and R⁶⁶ representing, independently, a hydrogen atom or an alkyl,allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radical,Z⁸ representing a bond, —O—, —NR⁶⁷— or —S—,R⁶³ and R⁶⁷ representing, independently, a hydrogen atom, an alkyl,allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radicalR⁶⁴ representing a hydrogen atom, an alkyl, allenylalkyl, alkenyl,alkenyl, alkynyl, cyanoalkyl, alkoxy or NR⁶⁸R⁶⁹ radical,R⁶⁸ and R⁶⁹ representing, independently, a hydrogen atom or an alkyl,allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radical,and R⁴⁸ represents a hydrogen atom or an alkyl, alkynyl or cyanoalkylradical;g and p, each time that they occur, being independently integers from 1to 6, and k andn, each time that they occur, being independently integers from 0 to 6;it being understood that when Het is such that the compound of generalformula (II) corresponds to general sub-formula (II)₄, then:A represents the 4-hydroxy-2,3-di-tertiobutyl-phenyl radical;B, R¹ and R² all represent H; and finallyΩ represents OH;it also being understood that at least one of the followingcharacteristics must be present:

-   -   Het is a thiazole, oxazole or isoxazoline ring, and        -   A represents a        -   radical in which R³ represents a hydrogen atom, the OH group            or an alkoxy or alkyl radical,        -   or A represents a        -   radical in which R⁴, R⁵, R⁶, R⁷ and R⁸ represent,            independently, a hydrogen atom, a halogen, the OH group or            an alkyl, alkoxy, cyano, nitro or NR¹⁰R¹¹ radical, R¹⁰ and            R¹¹ representing, independently, a hydrogen atom or an alkyl            radical        -   R⁹ represents a hydrogen atom or an alkyl radical,        -   and W doesn't exist, or represents a bond, or —O—, —S— or            —NR¹⁸—, in which R¹⁸ represents a hydrogen atom or an alkyl            radical,        -   or A represents a        -   radical in which Q represents OH or Q represents a phenyl            radical substituted by an OH radical and one or more of the            radicals chosen independently from a halogen atom and an OH,            alkyl, alkoxy or —NR¹⁰R¹¹ radical in which R¹⁰ and R¹¹            represent independently a hydrogen atom or an alkyl radical,        -   or also A represents a        -   radical in which R³² represents a hydrogen atom or an alkyl            radical and T represents a —(CH₂)_(m)— radical with m=1 or            2,        -   or finally A represents a        -   radical in which the R³³ radical represents a hydrogen atom            or an alkyl, -Σ-NR³⁴R³⁵ or -Σ-R³⁶R³⁷ radical, Σ representing            a linear or branched alkylene radical containing 1 to 6            carbon atoms, R³⁴ and R³⁵ representing, independently, a            hydrogen atom or an alkyl radical, R³⁶ and R³⁷ representing,            independently, a hydrogen atom or a carbocyclic or            heterocyclic aryl radical optionally substituted by one or            more substituents chosen from the alkyl, OH, halogen, nitro,            alkoxy or NR¹⁰R¹¹ radicals, R¹⁰ and R¹¹ representing,            independently, a hydrogen atom, an alkyl radical, or R¹⁰ and            R¹¹ forming together with the nitrogen atom an optionally            substituted heterocycle containing 4 to 7 members and 1 to 3            heteroatoms including the nitrogen atom already present, the            additional heteroatoms being chosen independently from the            group constituted by the O, N and S atoms, said heterocycle            being able to be for example azetidine, pyrrolidine,            piperidine, piperazine, morpholine or thiomorpholine,        -   and T represents a —(CH₂)_(m)— radical with m=1 or 2;        -   Het is an imidazole ring,        -   A represents a        -   radical in which Q represents OH,        -   and Ω represents NR⁴⁶R⁴⁷ in which R⁴⁶ or R⁴⁷ represents an            aminophenyl, nitrophenyl, aminophenylcarbonyl,            nitrophenylcarbonyl, aminophenylalkyl or nitrophenylalkyl            radical;        -   A represents a        -   radical B represents a carbocyclic aryl radical optionally            substituted 1 to 3 times by radicals chosen from the group            composed of a halogen atom, a linear or branched alkyl or            alkoxy radical containing 1 to 6 carbon atoms, a hydroxy,            cyano or nitro radical, an amino, alkylamino or dialkylamino            radical and a carbocyclic aryl radical, and one of R¹ and R²            represents one of the optionally substituted arylalkyl or            heteroarylalkyl radicals;        -   A represents a cycloalkyl or cycloalkylalkyl radical;        -   Ω represents NR⁴⁶R⁴⁷ and one of R⁴⁶ and R⁴⁷ represents an            alkenyl, allenyl, allenylalkyl, alkynyl, cyanoalkyl or            hydroxyalkyl radical;        -   one of R¹ and R² represents a cycloalkyl or cycloalkylalkyl            radical;        -   none of R¹ and R² represents H;        -   n=1 and A represents a biphenyl, phenoxyphenyl,            phenylthiophenyl, phenylcarbonylphenyl or            phenylsulphonylphenyl radical;        -   when Het is a thiazole ring and Ω represents the OR⁴⁸            radical in which R⁴⁸ is a cyanoalkyl radical, then the cyano            group is not attached to the carbon atom immediately            adjacent to the oxygen atom;            or the pharmaceutically acceptable salts of the compounds of            general formula (II).

Generally, the medicaments of General formula (II) having one of thefollowing additional characteristics are preferred:

i. n=0,

-   -   Het is an oxazole, thiazole or isoxazoline ring    -   A represents a    -   radical in which R³ represents a hydrogen atom, the OH group or        an alkoxy or alkyl radical,    -   or A represents a    -   radical in which R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ represent hydrogen        atoms and W doesn't exist, or represents a bond, or —O—, —S— or        —NR¹⁸— in which R¹⁸ represents a hydrogen atom or an alkyl        radical,    -   or A represents a    -   radical in which Q represents OH and two of the R¹⁹, R²⁰ and R²¹        radicals represent alkyl radicals,    -   or in which Q represents a phenyl radical substituted by an OH        radical and a radical or radicals chosen independently from a        halogen atom and an OH, alkyl, alkoxy or —NR¹⁰R¹¹ radical in        which R¹⁰ and R¹¹ represent independently a hydrogen atom or an        alkyl radical,    -   or also A represents a    -   radical in which R³² represents a hydrogen atom or an alkyl        radical and T represents —(CH₂)₂—,    -   or finally A represents a    -   radical in which T represents the —CH₂— radical and the R³³        radical represents a hydrogen atom or a -Σ-NR³⁴R³⁵ radical, Σ        representing a linear or branched alkylene radical containing 1        to 6 carbon atoms, and R³⁴ and R³⁵ representing, independently,        a hydrogen atom or an alkyl radical,    -   B represents H,    -   R¹ and R² represent, independently, a hydrogen atom or an alkyl        radical,    -   and Ω represents an NR⁴⁶R⁴⁷ radical in which one of R⁴⁶ and R⁴⁷        represents an alkyl, alkenyl, allenyl, allenylalkyl, alkynyl,        cyanoalkyl or hydroxyalkyl radical and the other represents a        hydrogen atom or an alkyl radical; or        ii. n=0,    -   A represents a    -   radical in which Q represents a hydrogen atom or an —OR²² or        —SR²² radical in which R²² represents an alkyl radical or an        aryl radical optionally substituted by one or more substituents        chosen from the alkyl, OH, halogen, nitro and alkoxy radicals,        R¹⁹, R²⁰ and R²¹ represent, independently, a hydrogen, a        halogen, an SR²⁶ radical, or an alkyl, cycloalkyl, alkenyl,        alkoxy, cyano, nitro, —SO₂NHR⁴⁹, —CONHR⁵⁵, —S(O)_(q)R⁵⁶,        —NH(CO)R⁵⁷, —CF₃, —OCF₃ or NR²⁷R²⁸ radical,    -   R²⁶ representing an alkyl radical,    -   R²⁷ and R²⁸ representing, independently, a hydrogen atom or an        alkyl radical or R²⁷ and R²⁸ forming together with the nitrogen        atom which carries them a heterocycle with 5 to 6 members chosen        from —CH₂—, —NH— and —O—,    -   R⁴⁹ and R⁵⁵ representing, independently each time that they        occur, a hydrogen atom or an alkyl or alkylcarbonyl radical,    -   q representing an integer from 0 to 2,    -   R⁵⁶ and R⁵⁷ representing, independently each time that they        occur, a hydrogen atom or an alkyl or alkoxy radical,    -   and one of R¹ and R² represents a cycloalkyl or cycloalkylalkyl        radical or none of R¹ and R² represent a hydrogen atom; or        finally        iii. n=1,    -   A represents an optionally substituted biphenyl radical or the        cyclohexylphenyl radical,    -   B represents a hydrogen atom,    -   R¹ and R² each represent a hydrogen atom,    -   and Ω represents an NR⁴⁶R⁴⁷ radical in which R⁴⁶ represents a        —COOR⁵¹ radical, R⁵¹ representing an alkyl, cycloalkyl,        cycloalkylalkyl or alkoxyalkyl radical and R⁴⁷ representing a        hydrogen atom.

In case i., it is preferred moreover that A represents a

radical in which Q represents OH and two of the R¹⁹, R²⁰ and R²¹radicals represent alkyl radicals.

In cases ii. and iii., it is preferred moreover that Het represents animidazole ring.

Preferably, the medicaments of general formula (II) will be chosen fromthe compounds described (sometimes in the form of salts) in Examples 1to 35, 52, 57, 61, 80, 82, 83, 85 to 87, 90, 94, 113, 115, 123, 127,130, 132, 134, 138, 139, 147, 152, 154, 161, 164, 169, 171 to 173, 176to 180, 203, 237 to 239, 243 to 247, 249, 251, 255, 258 to 262, 264 to271, 273 to 275 and 277 to 349, or the pharmaceutically acceptable saltsof these compounds.

More preferentially, the medicaments of general formula (II) will bechosen from the compounds described (sometimes in the form of salts) inExamples 1, 3, 6, 7, 11, 17, 24, 26 to 35, 57, 61, 82, 83, 85 to 87, 94,113, 123, 130, 132, 134, 138, 139, 152, 154, 164, 169, 171 to 173, 176to 178, 203, 237 to 239, 243 to 247, 249, 955, 258, 259, 261, 262, 264to 271, 273 to 275, 277 to 281, 283 to 288, 293 to 313, 321, 323, 324,332 and 338 to 340, or the pharmaceutically acceptable salts of thesecompounds.

Moreover, the same preferences as those indicated for the compounds ofgeneral formula (I) are moreover applicable by analogy to the compoundsof general formula (II).

The invention also relates, as new industrial products, to the compoundsof general formula (III)

in racemic, enantiomeric form or any combinations of these forms, inwhich Het is a heterocycle with 5 members comprising 2 heteroatoms andsuch that general formula (III) corresponds exclusively to one of thefollowing sub-formulae:

in whichA representseither a

radical in which R³ represents a hydrogen atom, the OH group or analkoxy or alkyl radical,or a

radical in which R⁴, R⁵, R⁶, R⁷ and R⁸ represent, independently, ahydrogen atom, a halogen, the OH group or an alkyl, alkoxy, cyano, nitroor NR¹⁰R¹¹ radical,R¹⁰ and R¹¹ representing, independently, a hydrogen atom, an alkylradical or a —COR¹² group, or R¹⁰ and R¹¹ forming together with thenitrogen atom an optionally substituted heterocycle with 4 to 7 membersand 1 to 3 heteroatoms including the nitrogen atom already present, theadditional heteroatoms being chosen independently from the groupconstituted by the O, N and S atoms,R¹² representing a hydrogen atom or an alkyl, alkoxy or NR¹³R¹⁴ radical,R¹³ and R¹⁴ represent, independently, a hydrogen atom or an alkylradical, or R¹³ and R¹⁴ forming together with the nitrogen atom anoptionally substituted heterocycle with 4 to 7 members and 1 to 3heteroatoms including the nitrogen atom already present, the additionalheteroatoms being chosen independently from the group constituted by theO, N and S atoms,R⁹ represents a hydrogen atom, an alkyl radical or a —COR¹⁵ group.R¹⁵ representing a hydrogen atom or an alkyl, alkoxy or NR¹⁶R¹⁷ radical,R¹⁶ and R¹⁷ representing, independently, a hydrogen atom or an alkylradical, or R¹⁶ and R¹⁷ forming together with the nitrogen atom anoptionally substituted heterocycle with 4 to 7 members and 1 to 3heteroatoms including the nitrogen atom already present, the additionalheteroatoms being chosen independently from the group constituted by theO, N and S atoms,and W doesn't exist, or represents a bond, or —O—, —S— or —NR¹⁸—, inwhich R¹⁸ represents a hydrogen atom or an alkyl radical;or a

radical in which Q represents H, —OR²², —SR²², —NR²³R²⁴, a phenylradical optionally substituted by one or more of the substituents chosenindependently from a halogen atom, an OH, cyano, nitro, alkyl, alkoxy or—NR¹⁰R¹¹ radical and a group of two substituents together representing amethylenedioxy or ethylenedioxy radical, or also Q represents a —COPh,—SO₂Ph or —CH₂Ph radical, said —COPh, —SO₂Ph or —CH₂Ph radical beingoptionally substituted on its aromatic part by one or more of thesubstituents chosen independently from an alkyl or alkoxy radical and ahalogen atom,R¹⁰ and R¹¹ representing, independently, a hydrogen atom, an alkylradical or a COR¹² group, or R¹⁰ and R¹¹ forming together with thenitrogen atom an optionally substituted heterocycle containing 4 to 7members and 1 to 3 heteroatoms including the nitrogen atom alreadypresent, the additional heteroatoms being chosen independently from thegroup constituted by the O, N and S atoms,R¹² representing a hydrogen atom, an alkyl or alkoxy or NR¹³R¹⁴ radical,R¹³ and R¹⁴ representing, independently, a hydrogen atom or an alkylradical, or R¹³ and R¹⁴ forming together with the nitrogen atom anoptionally substituted heterocycle with 4 to 7 members and 1 to 3heteroatoms including the nitrogen atom already present, the additionalheteroatoms being chosen independently from the group constituted by theO, N and S atoms,R²² representing a hydrogen atom, an alkyl radical or an aryl radicaloptionally substituted by one or more substituents chosen from thealkyl, OH, halogen, nitro and alkoxy radicals,R²³ and R²⁴ representing, independently, a hydrogen atom, an alkylradical or a —CO—R²⁵ radical,R²⁵ representing an alkyl radical,and R¹⁹, R²⁰ and R²¹ represent, independently, a hydrogen, a halogen,the OH or SR²⁶ group, or an alkyl, cycloalkyl, alkenyl, alkoxy, cyano,nitro, —SO₂NHR⁴⁹, —CONHR⁵⁵, S(O)_(q)R⁵⁶, —NH(CO)R⁵⁷, —CF₃, —OCF₃ orNR²⁷R²⁸ radical,R²⁶ representing a hydrogen atom or an alkyl radical,R²⁷ and R²⁸ representing, independently, a hydrogen atom, an alkylradical or a —COR²⁹ group, or R²⁷ and R²⁸ forming together with thenitrogen atom an optionally substituted heterocycle containing 4 to 7members and 1 to 3 heteroatoms including the nitrogen atom alreadypresent, the additional heteroatoms being chosen independently from thegroup constituted by the O, N and S atoms,R⁴⁹ and R⁵⁵ representing, independently each time that they occur, ahydrogen atom or an alkyl or alkylcarbonyl radical,q representing an integer from 0 to 2,R⁵⁶ and R⁵⁷ representing, independently each time that they occur, ahydrogen atom or an alkyl or alkoxy radical,R²⁹ representing a hydrogen atom, an alkyl, alkoxy or —NR³⁰R³¹ radical,R³⁰ and R³¹ representing, independently, a hydrogen atom or an alkylradical, or R³⁰ and R³¹ forming together with the nitrogen atom anoptionally substituted heterocycle containing 4 to 7 members and 1 to 3heteroatoms including the nitrogen atom already present, the additionalheteroatoms being chosen independently from the group constituted by theO, N and S atoms,or a

radical in which R³² represents a hydrogen atom or an alkyl radical, andT represents a —(CH₂)_(m)— radical with m=1 or 2,or finally a

radical in which R³³ represents a hydrogen atom or an alkyl, -Σ-NR³⁴R³⁵or -Σ-CHR³⁶R³⁷ radical,Σ representing a linear or branched alkylene radical containing 1 to 6carbon atoms,R³⁴ and R³⁵ representing, independently, a hydrogen atom or an alkylradical,R³⁶ and R³⁷ representing, independently, a hydrogen atom or acarbocyclic or heterocyclic aryl radical optionally substituted by oneor more substituents chosen from the alkyl, OH, halogen, nitro, alkoxyor NR¹⁰R¹¹ radicals,R¹⁰ and R¹¹ representing, independently, a hydrogen atom, an alkylradical or a —COR¹² group, or R¹⁰ and R¹¹ forming together with thenitrogen atom an optionally substituted heterocycle containing 4 to 7members and 1 to 3 heteroatoms including the nitrogen atom alreadypresent, the additional heteroatoms being chosen independently from thegroup constituted by the O, N and S atoms,R¹² representing a hydrogen atom or an alkyl, alkoxy or NR¹³R¹⁴ radical,R¹³ and R¹⁴ representing, independently, a hydrogen atom or an alkylradical, or R¹³ and R¹⁴ forming together with the nitrogen atom anoptionally substituted heterocycle containing 4 to 7 members and 1 to 3heteroatoms including the nitrogen atom already present, the additionalheteroatoms being chosen independently from the group constituted by theO, N and S atoms,and T represents a —(CH₂)_(m)— radical with m=1 or 2,or also A represents an alkyl, cycloalkyl or cycloalkylalkyl radical;X represents S or NR³⁸,R³⁸ representing a hydrogen atom or an alkyl, cyanoalkyl, aralkyl,alkylcarbonyl or aralkylcarbonyl radical,Y represents O or S;R¹ represents a hydrogen atom, an alkyl, aminoalkyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, trifluoromethylalkyl, alkenyl, allenyl,allenylalkyl, alkynyl, cyanoalkyl, —(CH₂)_(g)-Z¹R³⁹, —(CH₂)_(g)—COR⁴⁰,—(CH₂)_(g)—NHCOR⁷⁰, aryl, aralkyl, arylcarbonyl, heteroarylalkyl oraralkylcarbonyl radical, the aryl group of the aryl, aralkyl,arylcarbonyl, heteroarylalkyl or aralkylcarbonyl radicals being itselfoptionally substituted by one or more substituents chosen from the groupconstituted by the alkyl, halogen, alkoxy, nitro, cyano, cyanoalkyl,amino, alkylamino, dialkylamino, —(CH₂)_(k)-Z²R³⁹ or —(CH₂)_(k)—COR⁴⁰radicals,Z¹ and Z² representing a bond, —O—, —NR⁴¹— or —S—,R³⁹ and R⁴¹ representing, independently each time that they occur, ahydrogen atom or an alkyl, alkenyl, alkynyl or cyanoalkyl radical,R⁴⁰ representing, independently each time that it occurs, a hydrogenatom or an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl, cyanoalkyl,alkoxy or NR⁴²R⁴³ radical,R⁴² and R⁴³ representing, independently each time that they occur, ahydrogen atom or an alkyl, allenyl, allenylalkyl, alkenyl, alkynyl orcyanoalkyl radical,and R² represents a hydrogen atom, an alkyl, aminoalkyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, trifluoromethylalkyl or —(CH₂)_(g)—NHCOR⁷¹radical, or also one of the aralkyl or heteroarylalkyl radicalsoptionally substituted on the aryl or heteroaryl group by one or more ofthe groups chosen independently from the group composed of a halogenatom and an alkyl, alkoxy, hydroxy, cyano, nitro, amino, alkylamino ordialkylamino radical,R⁷⁰ and R⁷¹ representing independently an alkyl or alkoxy radical;or R¹ and R², taken together with the carbon atom which carries them,form a carbocycle with 3 to 7 members;B represents a hydrogen atom, an alkyl radical, a —(CH₂)_(g)-Z³R⁴⁴radical or a carbocyclic aryl radical optionally substituted 1 to 3times by the radicals chosen from the group composed of a halogen atom,a linear or branched alkyl or alkoxy radical containing 1 to 6 carbonatoms, a hydroxy, cyano or nitro radical, an amino, alkylamino ordialkylamino radical and a carbocyclic aryl radical,Z³ representing a bond, —O—, —NR⁴⁵— or —S—,R⁴⁴ and R⁴⁵ representing, independently, a hydrogen atom or an alkyl,alkenyl, alkynyl, allenyl, allenylalkyl or cyanoalkyl radical;Ω represents one of the NR⁴⁶R⁴⁷ or OR⁴⁸ radicals, in which:R⁴⁶ and R⁴⁷ represent, independently, a hydrogen atom or an alkyl,cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, allenyl, allenylalkyl,cyanoalkyl, —(CH₂)_(g)-Z⁴R⁵⁰, —(CH₂)_(k)—COR⁵¹, —(CH₂)_(k)—COOR⁵¹,—(CH₂)_(k)—CONHR⁵¹ or —SO₂R⁵¹ radical, or also a radical chosen from thearyl, aralkyl, aryloxyalkyl, arylcarbonyl, arylimino, aralkylcarbonyl,heteroaryl and in particular pyridinyl, pyridinylalkyl orpyridinylcarbonyl radicals, the aryl or heteroaryl group of said aryl,aralkyl, aryloxyalkyl, arylcarbonyl, arylimino, aralkylcarbonyl,heteroaryl, pyridinylalkyl or pyridinylcarbonyl radicals beingoptionally substituted by one or more of the substituents chosenindependently from halogen, alkyl, alkoxy, hydroxy, nitro, cyano,cyanoalkyl, amino, alkylamino, dialkylamino, —(CH₂)_(k)-Z⁵R⁵⁰,—(CH₂)_(k)—COR⁵¹ and —(CH₂)_(k)—COOR⁵¹,Z⁴ and Z⁵ representing a bond, —O—, —NR⁵²— or —S—,or R⁴⁶ and R⁴⁷ taken together form with the nitrogen atom a non aromaticheterocycle with 4 to 8 members, the elements of the chain being chosenfrom a group composed of —CH(R⁵³)—, —NR⁵⁴—, —O—, —S— and —CO—,R⁵⁰ and R⁵², representing, independently each time that they occur, ahydrogen atom or an alkyl, alkenyl, alkynyl, allenyl, allenylalkyl orcyanoalkyl radical,R⁵¹ representing, independently each time that they occur, a hydrogenatom, one of the cycloalkyl or cycloalkylalkyl radicals in which thecycloalkyl radical contains 3 to 7 carbon atoms, a linear or branchedalkyl radical containing 1 to 8 carbon atoms, an alkenyl, alkynyl,allenyl, allenylalkyl, cyanoalkyl, alkoxyalkyl or NR⁵⁸R⁵⁹ radical, oralso an aryl or aralkyl radical, said aryl or aralkyl radical being ableto be substituted by one or more the substituents chosen independentlyfrom a halogen atom and an alkyl or alkoxy radical,R⁵⁸ and R⁵⁹ representing, independently, a hydrogen atom or an alkyl,alkenyl, alkynyl, allenyl, allenylalkyl or cyanoalkyl radical,R⁵³ and R⁵⁴ representing, independently, a hydrogen atom or a—(CH₂)_(k)-Z⁷R⁶⁰ or —(CH₂)_(k)—COR⁶¹ radical,Z⁷ representing a bond, —O—, —NR⁶²— or —S—,R⁶⁰ and R⁶² representing, independently, a hydrogen atom or an alkyl,alkenyl, allenyl, allenylalkyl, alkynyl, cyanoalkyl, aryl, aralkyl,arylcarbonyl, aralkylcarbonyl, pyridinyl, pyridinylalkyl orpyridinylcarbonyl radical, the aryl or pyridinyl group of the aryl,aralkyl, arylcarbonyl, aralkylcarbonyl, pyridinyl, pyridinylalkyl orpyridinylcarbonyl radicals being optionally substituted by one or moresubstituents chosen from the group constituted by the alkyl, halogen,nitro, alkoxy, cyano, cyanoalkyl, —(CH₂)_(k)-Z⁸R⁶³ and —(CH₂)_(k)—COR⁶⁴radicals,R⁶¹ representing a hydrogen atom, an alkyl, allenyl, allenylalkyl,alkenyl, alkynyl, cyanoalkyl, alkoxy or NR⁶⁵R⁶⁶ radical,R⁶⁵ and R⁶⁶ representing, independently, a hydrogen atom or an alkyl,allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radical,Z⁸ representing a bond, —O—, —NR⁶⁷— or —S—,R⁶³ and R⁶⁷ representing, independently, a hydrogen atom, an alkyl,allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radical,R⁶⁴ representing a hydrogen atom, an alkyl, allenylalkyl, alkenyl,alkenyl, alkynyl, cyanoalkyl, alkoxy or NR⁶⁸R⁶⁹ radical,R⁶⁸ and R⁶⁹ representing, independently, a hydrogen atom or an alkyl,allenyl, allenylalkyl, alkenyl, alkynyl or cyanoalkyl radical,and R⁴⁸ represents a hydrogen atom or an alkyl, alkynyl or cyanoalkylradical;g and p, each time that they occur, being independently integers from 1to 6, and k and n, each time that they occur, being independentlyintegers from 0 to 6;it being understood that when Het is such that the compound of generalformula (III) corresponds to general sub-formula (III)₄, then:A represents the 4-hydroxy-2,3-di-tertiobutyl-phenyl radical;B, R¹ and R² all represent H; and finallyΩ represents OH;it being also understood that at least one of the followingcharacteristics must be present:

-   -   when A represents a    -   radical in which Q represents OH,    -   Ω does not represent an NR⁴⁶R⁴⁷ radical in which R⁴⁶ or R⁴⁷ are        chosen from a hydrogen atom and an alkyl radical or an NR⁴⁶R⁴⁷        radical in which R⁴⁶ or R⁴⁷ represents an aminophenyl,        nitrophenyl, aminophenylcarbonyl, nitrophenylcarbonyl,        aminophenylalkyl or nitrophenylalkyl radical;    -   A represents a    -   radical B represents a carbocyclic aryl radical optionally        substituted 1 to 3 times by radicals chosen from the group        composed of a halogen atom, a linear or branched alkyl or alkoxy        radical containing 1 to 6 carbon atoms, a hydroxy, cyano or        nitro radical, an amino, alkylamino or dialkylamino radical and        a carbocyclic aryl radical, and one of R¹ and R² represents one        of the optionally substituted arylalkyl or heteroarylalkyl        radicals;    -   A represents a cycloalkyl or cycloalkylalkyl radical;    -   Ω represents NR⁴⁶R⁴⁷ and one of R⁴⁶ and R⁴⁷ represents an        alkenyl, allenyl, allenylalkyl, alkynyl, cyanoalkyl or        hydroxyalkyl radical;    -   one of R¹ and R² represents a cycloalkyl or cycloalkylalkyl        radical;    -   none of R¹ and R² represent H;    -   n=1 and A represents a biphenyl, phenoxyphenyl,        phenylthiophenyl, phenylcarbonylphenyl or phenylsulphonylphenyl        radical;    -   when Het is a thiazole ring and Ω represents the OR⁴⁸ radical in        which R⁴⁸ is a cyanoalkyl radical, then the cyano group is not        attached to the carbon atom immediately adjacent to the oxygen        atom;        or the salts of the compounds of general formula (III).

According to one of the preferred variants of the invention, thecompounds of general formula (III) will be both ROS and MAO inhibitorsand have at least one of the following characteristics:

-   -   A representing the:    -    radical in which Q represents OH, two of the R¹⁹, R²⁰ and R²¹        radicals represent radicals chosen independently from the alkyl,        alkoxy, alkylthio, amino, alkylamino or dialkylamino radicals        and the third represents a radical chosen from a hydrogen atom        and the alkyl, alkoxy, alkylthio, amino, alkylamino or        dialkylamino radicals;    -   n representing 0 or 1;    -   R¹ and R² both representing H;    -   Ω representing OH or the NR⁴⁶R⁴⁷ radical in which one of R⁴⁶ and        R⁴⁷ represents a cyanoalkyl radical and the other represents H        or alkyl or also in which R⁴⁶ and R⁴⁷ taken together form with        the nitrogen atom a non aromatic heterocycle with 4 to 8        members, the elements of the chain being chosen from a group        composed of —CH(R⁵³)—, —NR⁵⁴—, —O—, —S—, —CO—, R⁵³ and R⁵⁴ being        as defined in general formula (III).

According to another preferred variant of the invention, the compoundsof general formula (III) will be modulators of the sodium channels andpreferably have one of the following two characteristics:

-   -   n=0,    -   A represents a    -   radical in which Q represents a hydrogen atom or an —OR²² or        —SR²² radical in which R²² represents an alkyl radical or an        aryl radical optionally substituted by one or more substituents        chosen from the alkyl, OH, halogen, nitro and alkoxy radicals,        R¹⁹, R²⁰ and R²¹ represent, independently, a hydrogen, a        halogen, an SR²⁶ radical, or an alkyl, cycloalkyl, alkenyl,        alkoxy, cyano, nitro, —SO₂NHR⁴⁹, —CONHR⁵⁵, —S(O)_(q)R⁵⁶,        —NH(CO)R⁵⁷, —CF₃, —OCF₃ or NR²⁷R²⁸ radical, R²⁶ representing an        alkyl radical,    -   R²⁷ and R²⁸ representing, independently, a hydrogen atom or an        alkyl radical or R²⁷ and R²⁸ forming together with the nitrogen        atom which carries them a heterocycle with 5 to 6 members chosen        from —CH₂—, —NH— and —O—,    -   R⁴⁹ and R⁵⁵ representing, independently each time that they        occur, a hydrogen atom or an alkyl or alkylcarbonyl radical,    -   q representing an integer from 0 to 2,    -   R⁵⁶ and R⁵⁷ representing, independently each time that they        occur, a hydrogen atom or an alkyl or alkoxy radical,    -   and one of R¹ and R² represents a cycloalkyl or cycloalkylalkyl        radical or none of R¹ and R² represents a hydrogen atom; or        finally    -   n=1,    -   A represents a biphenyl or cyclohexylphenyl radical,    -   B represents a hydrogen atom,    -   R¹ and R² each represent a hydrogen atom,    -   and Ω represents an NR⁴⁶R⁴⁷ radical in which R⁴⁶ represents        a-COOR⁵¹ radical, R⁵¹ representing an alkyl, cycloalkyl,        cycloalkylalkyl or alkoxyalkyl radical and R⁴⁷ representing a        hydrogen atom.

More preferentially, the compounds of general formula (III) which aremodulators of the sodium channels are such that Het represents animidazole ring (i.e. that they correspond to one of general formulae(III)₁ or (III)₂ in which X represents an NR³⁸ radical in which R³⁸ isas defined previously).

Generally, the compounds of general formula (III) will be preferablychosen from the compounds described (sometimes in the form of salts) inExamples 1 to 7, 9, 10, 24, 26 to 35, 52, 57, 61, 80, 82, 83, 85 to 87,90, 94, 113, 115, 123, 127, 130, 132, 134, 138, 139, 147, 152, 154, 161,164, 169, 171 to 173, 176 to 180, 203, 237 to 239, 243 to 247, 249, 251,255, 258 to 262, 264 to 271, 273 to 275, 277 to 333 and 335 to 349, orthe salts of these compounds.

More preferentially, the compounds of general formula (III) will bechosen from the compounds described (sometimes in the form of salts) inExamples 1, 3, 6, 7, 24, 26 to 35, 57, 61, 82, 83, 85 to 87, 94, 113,123, 130, 132, 134, 138, 139, 152, 154, 164, 169, 171 to 173, 176 to178, 203, 237 to 239, 243 to 247, 249, 255, 258, 259, 261, 262, 264 to271, 273 to 275, 277 to 281, 283 to 288, 293 to 313, 321, 323, 324, 332and 338 to 340, or the salts of these compounds.

The same preferences as those indicated for the compounds of generalformula (I) and (II) are moreover applicable by analogy to the compoundsof general formula (III).

In certain cases, the compounds according to the present invention (i.e.the compounds of general formula (I), (II) or (III)) can containasymmetrical carbon atoms. As a result, the compounds according to thepresent invention have two possible enantiomeric forms, i.e. the “R” and“S” configurations. The present invention includes the two enantiomericforms and all combinations of these forms, including the racemic “RS”mixtures. For the sake of simplicity, when no specific configuration isindicated in the structural formulae, it should be understood that thetwo enantiomeric forms and their mixtures are represented.

The invention also relates to of the pharmaceutical compositionscontaining, as active ingredient, a compound of general formula (II) ora pharmaceutically acceptable salt of a compound general formula (II),as well as the use of the compounds of general formula (II) forpreparing a medicament intended to inhibit the monoamine oxydases, inparticular monoamine oxydase B, to inhibit lipidic peroxidation, to havea modulatory activity on the sodium channels or to have two of the threeor all three aforementioned activities.

The invention relates moreover, as medicaments, to the compounds ofgeneral formula (III) or their pharmaceutically acceptable salts.Similarly it relates to the pharmaceutical compositions containing, asactive ingredient, a compound of general formula (III) or apharmaceutically acceptable salt of a compound of general formula (III),as well as to the use of the compounds of general formula (III) forpreparing a medicament intended to inhibit monoamine oxydases, inparticular monoamine oxydase B, to inhibit lipidic peroxidation, to havea modulatory activity on the sodium channels or to have two of the threeor all three of the aforementioned activities.

In particular, the compounds of general formula (I), (II) or (III) canbe used for preparing a medicament intended to treat one of thefollowing disorders or one of the following diseases: Parkinson'sdisease, senile dementia, Alzheimer's disease, Huntington's chorea,amyotrophic lateral sclerosis, schizophrenia, depressions, psychoses,migraine or pains and in particular neuropathic pains.

By pharmaceutically acceptable salt, is meant in particular the additionsalts with inorganic acids such as hydrochloride, hydrobromide,hydroiodide, sulphate, phosphate, diphosphate and nitrate or withorganic acids such as acetate, maleate, fumarate, tartrate, succinate,citrate, lactate, methanesulphonate, p-toluenesulphonate, pamoate andstearate. Also included in the field of the present invention, when theycan be used, are the salts formed from bases such as sodium or potassiumhydroxide. For other examples of pharmaceutically acceptable salts,reference can be made to “Salt selection for basic drugs”, Int. J.Pharm. (1986), 33, 201-217.

The pharmaceutical composition can be in the form of a solid, forexample powders, granules, tablets, gelatin capsules, liposomes orsuppositories. Appropriate solid supports can be, for example, calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine and wax.

The pharmaceutical compositions containing a compound of the inventioncan also be presented in liquid form, for example, solutions, emulsions,suspensions or syrups. Appropriate liquid supports can be, for example,water, organic solvents such as glycerol or glycols, similarly theirmixtures, in varying proportions, in water.

The administration of a medicament according to the invention can bedone by topical, oral, parenteral route, by intramuscular injection,etc.

The administration dose envisaged for a medicament according to theinvention is comprised between 0.1 mg to 10 g according to the type ofactive compound used.

In accordance with the invention, the compounds of general formula (I)can be prepared by the processes described below.

PREPARATION OF THE COMPOUNDS OF THE INVENTION

Generalities

The preparations of the compounds of the invention which correspond togeneral formulae (I), (II) or (III) in which Ω represents OH are carriedout in a similar fashion to those described in the PCT PatentApplication WO 99/09829 and the European Patent Application EP 432 740.

As regards the compounds of the invention which correspond to generalformulae (I), (II) and (III) and in which Het is an imidazole ring, aperson skilled in the art can also usefully consult the PCT PatentApplication WO 99/64401.

The preparations of the other compounds of the invention whichcorrespond to general formulae (I), (II) and (III) are carried out in asimilar fashion to those described in the PCT Patent Application WO98/58934 (cf. in particular on pages 39 to 45 of this document thesyntheses of intermediates of general formulae (XXV) and (XXVIII)) oraccording to the procedures described hereafter.

Preparation of the Compounds of General Formula (I)

The compounds of general formula (I) can be prepared by the 8 synthesisroutes illustrated below (Diagram 1) starting from the intermediates ofgeneral formula (IV), (V), (VI), (VII), (VIII), (IX), (X) and (I)α inwhich A, B, Q, R¹, R², Het and n are as defined above, L is a partinggroup such as for example a halogen, Alk is an alkyl radical, Gp is aprotective group for an amine function, for example a2-(trimethylsilyl)ethoxymethyl (SEM) group, and Gp′ a protective groupfor an alcohol function, for example a group of benzyl, acetate or alsosilyl type such as tert-butyldimethylsilyl, and finally A represents abond or a —(CH₂)_(x)—, —CO—(CH₂)_(x)—, —(CH₂)_(y)—O— or —C(═NH)—radical. Of course, a person skilled in the art can choose to useprotective groups other than Gp and Gp from those which are known, andin particular those mentioned in: Protective groups in organicsynthesis, 2nd ed., (John Wiley & Sons Inc., 1991).

Route 1: Het is Imidazole and K is NR⁴⁶R⁴⁷ but Not a Radical ofCarbamate Type

The amines and carboxamides of general formula (I), Diagram 2, in whichA, B, R¹, R², R⁴⁶, R⁴⁷, Het and n are as defined above, are prepared bydeprotection for example, in the case where Gp represents SEM, withtert-butylammonium fluoride (TBAF) in THF, of the amine of generalformula (IV) in order to release the amine of the heterocycle of thecompound of general formula (I). The protected amines of general formula(IV) are accessible by a general synthesis route described in Biorg. andMed. Chem. Lett., 1993, 3, 915 and Tetrahedron Lett., 1993. 34, 1901 andmore particularly in the PCT Patent Application WO 98/58934.

Route 2: Het is Imidazole, Oxazole or Thiazole and Ω is NR⁴⁶R⁴⁷

The amines and carboxamides of general formula (I), Diagram 3, in whichA, B, R¹, R², R⁴⁶, Het, g, k and n are as defined above, Δ represents analkyl, cycloalkylalkyl, arylalkyl, aryl, allenyl, allenylalkyl, alkenyl,alkynyl, cyanoalkyl or hydroxyalkyl radical and Δ′ represents an alkyl,cycloalkylalkyl, arylalkyl or aryl radical when g or k do not represent0, or Δ′ represents an alkyl, cycloalkylalkyl, arylalkyl radical or anaryl radical preferably deactivated (i.e. an aryl radical substituted byan electron attractor group such as for example a nitro or cyano group)when g or k represents 0, are prepared by condensation of the amines ofgeneral formula (V) with carboxylic acids (or the corresponding acidchlorides) of general formula (XIII) under standard conditions ofpeptide synthesis, with the aldehydes of general formula (XII) in thepresence of a reducing agent such as sodium triacetoxyborohydride orsodium borohydride, in a lower aliphatic alcohol such as methanol andoptionally in the presence of molecular sieves, or with halogenatedderivatives (Hal=halogen atom) of general formula (XI). In particular,when A represents an allenyl, allenylalkyl, alkenyl, alkynyl, cyanoalkylor hydroxyalkyl radical, the compounds of general formula (V) areconverted to the corresponding compounds of general formula (I) byreaction with the halogenated derivatives of general formula (XI) in asolvent such as acetonitrile, dichloromethane or acetone and in thepresence of a base such as for example triethylamine or potassiumcarbonate at a temperature comprised between ambient temperature and thereflux temperature of the solvent.

The derivatives of general formula (V) are in particular accessible by ageneral synthesis route described in Biorg. and Med. Chem. Lett., 1993,3, 915 and Tetrahedron Lett., 1993. 34, 1901, and more particularly inthe Patent Application WO 98/58934. When R⁴⁶═H, the compounds of generalformula (V) can be prepared, for example, according to a protocoldescribed in the Patent Application WO 98/58934 (using the appropriateamino acid in place of N—Boc-sarcosinamide).

In the particular case where R⁴⁷ represents a cycloalkyl radical, theamines of general formula (I), Diagram 3a, in which A, B, R¹, R², R⁴⁶,Het and n are as defined above and i represents an integer from 0 to 4are prepared by condensation of the amines of general formula (V) withthe cycloalkylketones of general formula (XIV) in the presence of areducing agent such as sodium triacetoxyborohydride or sodiumborohydride in a lower aliphatic alcohol such as methanol and optionallyin the presence of molecular sieves at ambient temperature.

The sulphonamides of general formula (I), Diagram 3b, in which A, B, R¹,R², R⁴⁶, Het and n are as defined above, R⁴⁷ represents an —SO₂-Δradical and Δ represents an alkyl, cycloalkyl, cycloalkylalkyl orarylalkyl radical, are prepared by condensation of the amines of generalformula (V) with the sulphochlorides of general formula (XV) understandard conditions, for example in a solvent such as dimethylformamideat ambient temperature.

The ureas of general formula (I), Diagram 3c, in which A, B, R¹, R²,R⁴⁶, Het and n are as defined above, R⁴⁷ represents a —CO—NH-Δ radicaland Δ represents an alkyl, cycloalkyl, cycloalkylalkyl or arylalkylradical, are prepared by reaction of the amines of general formula (V)with the isocyanates of general formula (XVI) in an inert solvent suchas dichloromethane or 1,2-dichloroethane.

Route 3: Het is Oxazole or Thiazole, R¹ and R² are both H and Ω is OH.

The alcoholic derivatives of general formula (I), Diagram 4, in which A,B, Het and n are as defined above and R¹ and R² are hydrogen atoms areobtained by reduction of the acids or esters of general formula (VI)(accessible by a general synthesis route described in J. Med. Chem.,1996, 39, 237-245 and the PCT Patent Application WO 99/09829). Thisreduction can, for example, be carried out by the action of boronhydride or lithium aluminium hydride or also diisobutylaluminium hydridein an aprotic polar solvent such as tetrahydrofuran.

Route 4: Het is Oxazole or Thiazole and Ω is NR⁴⁶R⁴⁷.

The amines of general formula (I), Diagram 5, in which A, B, R¹, R²,R⁴⁶, R⁴⁷, Het, and n are as defined above, are prepared by condensationof the primary or secondary amines of general formula R⁴⁶—NHR⁴⁷ with thecompounds of general formula (VII) (in which L preferably represents ahalogen atom Hal, but can also represent a mesylate or tosylate group)according to a general synthesis route described in J. Med. Chem., 1996,39, 237-245 and the PCT Patent Application WO 99/09829 or the U.S. Pat.No. 4,123,529. This synthesis route can in particular be used when R⁴⁶and R⁴⁷ taken together form with the nitrogen atom which carries them anon-aromatic heterocycle with 4 to 8 members. The reaction typicallytakes place in an anhydrous solvent (for example dimethylformamide,dichloromethane, tetrahydrofuran or acetone) in the presence of a base(for example Na₂CO₃ or K₂CO₃ in the presence of triethylamine), andpreferably while heating.

Route 5: Het is Imidazole and Ω is a Radical of Carbamate Type

When Ω is a radical of carbamate type, the acids of general formula(VIII) can be cyclized in the form of derivatives of imidazoles ofgeneral formula (I), Diagram 6, by the addition of caesium carbonatefollowed by a condensation with an α-halogenoketone of formulaA-CO—CH(B)—[Br, Cl] followed by the addition of a large excess ofammonium acetate (for example 15 or 20 equivalents per equivalent ofacid of general formula (VIII)). This reaction is preferably carried outin a mixture of xylenes and while heating (one can also, if appropriate,simultaneously eliminate the water formed during the reaction).

Route 6: Het is Imidazole, Oxazole or Thiazole and Ω is NR⁴⁶R⁴⁷

When Ω is an NR⁴⁶R⁴⁷ radical in which R⁴⁷ is a radical comprising atermination of aminophenylene, alkylaminophenylene ordialkylaminophenylene type, the compounds of general formula (I), inwhich A, B, Het, n, R¹, R² and R⁴⁶ are as defined above and Λ representsa bond or a —(CH₂)_(x)—, —CO—(CH₂)_(x)—, —(CH₂)_(y)—O— or —C(═NH)—radical, x and y being integers from 0 to 6, can be obtained, Diagram 7,by reduction of the compound of general formula (IX), for example by theaction of hydrogen in the presence of a catalyst of palladium on carbontype in a solvent such as for example methanol, ethanol, dichloromethaneor tetrahydrofuran. Reduction of the nitro function can also be carriedout, for example, by heating the product in an appropriate solvent suchas ethyl acetate with a little ethanol in the presence of SnCl₂ (J.Heterocyclic Chem. (1987), 24, 927-930; Tetrahedron Letters (1984), 25(8), 839-842) or in the presence of SnCl₂/Zn (Synthesis. (1996), 9,1076-1078), using NaBH₄—BiCl₃ (Synth. Com. (1995) 25 (23), 3799-3803) ina solvent such as ethanol, or then by using Raney Ni with hydrazinehydrate added to it (Monatshefte für Chemie, (1995), 126, 725-732), oralso using indium in a mixture of ethanol and ammonium chloride underreflux (Synlett (1998) 9, 1028).

When R⁴⁷ is a radical of aminophenylene, alkylaminophenylene ordialkylaminophenylene type (Alk and Alk′ are identical or differentalkyl radicals), the compound of general formula (IX) is reduced inorder to produce the aniline derivative of general formula (I) andoptionally mono- or di-alkylated according to standard reactions knownto a person skilled in the art. The mono-alkylation is carried out byreducing amination with an aldehyde or by a nucleophilic substitution byreaction with an equivalent of halogenoalkyl Alk-Hal. A secondalkylation can then be carried out if appropriate using a halogenoalkylAlk′-Hal.

In the particular case where Alk=Alk′=—CH₃ and where A does notrepresents —CH₂—, the nitro derivative of general formula (IX) will betreated with suitable quantities of paraformaldehyde under a flow ofhydrogen in a solvent such as ethanol and in the presence of a catalystof palladium on carbon type (Diagram 7a).

Route 7: Het is Imidazole, Oxazole or Thiazole and Ω is OH

This route can be used when Ω is OH. Contrary to route 3, R¹ and R²cannot be hydrogen atoms. In this case, the compounds of general formula(I) can be obtained, Diagram 8, by deprotection of the protected alcoholof general formula (X).

In the case where Gp′ is a protective group of silyl type, thedeprotection can be carried out, for example, by addingtetra-tert-butylammonium fluoride in a solvent such as tetrahydrofuran.In the case where Gp′ is a protective group of benzyl type, thedeprotection will be carried out by hydrogenation in a solvent such asfor example methanol, ethanol, dichloromethane or tetrahydrofuran. Inthe case where Gp′ is a protective group of acetate type, thedeprotection can be carried out, for example, using sodium or potassiumcarbonate in an alcoholic solvent such as methanol. For other cases, aperson skilled in the art will usefully consult the following document:Protective groups in organic synthesis, 2nd ed., (John Wiley & SonsInc., 1991).

Route 8: Het is Imidazole, Oxazole or Thiazole and Ω is OR⁴⁸ with R⁴⁸H

The compounds of general formula (I) in which Ω is an OR⁴⁸ radical withR⁴⁸ H are obtained, for example, Diagram 9, from alcohols of generalformula (I)a (which are compounds of general formula (I) as definedpreviously in which Q represents OH) by reacting the latter with ahalide of general formula R⁴⁸-Hal (Hal=Br, Cl or I) in a solvent such asdichloromethane, acetonitrile, anhydrous tetrahydrofuran or anhydrousether and in the presence of a base such as potassium or sodiumcarbonate, sodium hydride or triethylamine.

In the case where the A, B, R¹ and R² radicals contain alcohol, phenol,amine or aniline functions, it may be necessary to addprotection/deprotection stage for these functions according to standardmethods known to a person skilled in the art (stages not represented inDiagram 9).

Preparation of the Synthesis IntermediatesPreparation of the Imidazoles and Thiazoles of General Formula (V)General Outline

The non-commercial ketonic derivative of general formula (V.i) or (V.i),in which A and B are as defined in general formula (I) is converted,Diagram 3.1, to the corresponding α-bromo-ketone of general formula(V.ii) or (V.ii), by reaction with a bromination agent such as CuBr₂ (J.Org. Chem. (1964), 29, 3459), bromine (J. Het. Chem. (1988), 25, 337),N-bromosuccinimide (J. Amer. Chem. Soc. (1980), 102, 2838) in thepresence of acetic acid in a solvent such as ethyl acetate ordichloromethane, HBr or Br₂ in ether, ethanol or acetic acid (Biorg.Med. Chem. Lett. (1996), 6(3), 253-258; J. Med. Chem. (1988), 31(10),1910-1918) J. Am. Chem. Soc. (1999), 121, 24) or also using abromination resin (J. Macromol. Sci. Chem. (1977), A11, (3) 507-514). Inthe particular case where A is a p-dimethylaminophenyl radical, it ispossible to use the operating method appearing in the publicationTetrahedron Lett., 1998, 39 (28), 4987. The amine of general formula (V)is then obtained according to the procedures shown in Diagrams 3.2(imidazoles) and 3.3 (thiazoles) hereafter.

Alternatively to the synthesis shown in Diagram 3.1, a person skilled inthe art can, if appropriate, use an α-chloro-ketone in place of anα-bromo-ketone.

Obtaining the Imidazoles of General Formula (V)

The acid of general formula (V.iii), in which Gp represents a protectivegroup for an amine function, for example a protective group of carbamatetype, is treated, Diagram 3.2, with Cs₂CO₃ in a solvent such as methanolor ethanol. The α-halogeno-ketone of general formula (V.ii) in an inertsolvent such as dimethylformamide is added to the caesium saltrecovered. The intermediate ketoester is cyclized by heating to refluxin xylene (mixture of isomers) in the presence of a large excess ofammonium acetate (15 or 20 equivalents for example) in order to producethe imidazole derivative of general formula (V.iv) (the water formedbeing optionally eliminated during the reaction).

In the case where R³⁸ is not H, the amine function of the imidazole ringof the compound of general formula (V.iv) is substituted by reactionwith the halogenated derivative R³⁸-Hal (Hal=halogen atom); theprotected amine function is then deprotected under standard conditions(for example: trifluoroacetic acid or HCl in an organic solvent when itis a protective group of carbamate type, or also hydrogenation in thepresence of palladium on carbon when the protective group is a benzylcarbamate).

Obtaining the Thiazoles of General Formula (V) Intended for thePreparation of Compounds of General Formulae (I)₁ or (I)₂:

The thiocarboxamide of general formula (V.v), in which Gp represents aprotective group for an amine function, for example a protective groupof carbamate type, obtained for example by reaction of the correspondingcarboxamide with Lawesson reagent or with (P₂S₅)₂, is reacted, Diagram3.3, with the α-bromo-ketone of general formula (V.ii) or (V.ii)₂according to an experimental protocol described in the literature (J.Org. Chem., (1995), 60, 5638-5642). The protected amine function is thendeprotected under standard conditions in a strong acid medium (forexample: trifluoroacetic acid or HCl in an organic solvent when it is aprotective group of carbamate type), releasing the amine of generalformula (V).

Obtaining the Thiazoles (V) Intended for the Preparation of Compounds ofGeneral Formula (I)₃:

These compounds are obtained according to a method summarized in Diagram3.4 below. The carboxamide of general formula (VII.ii) is firstlytreated, for example, with Lawesson reagent or with (P₂S₅)₂ then thethiocarboxamide of general formula (VII.iii) obtained is reacted withthe halogenated derivative of general formula (V.vii) (cf. Biorg. Med.Chem. Lett. (1996), 6(3), 253-258; J. Med. Chem. (1988), 31(10),1910-1918; Tetrahedron Lett., (1993), 34 (28), 4481-4484; or J. Med.Chem. (1974), 17, 369-371; or also Bull. Acd. Sci. USSR Div. Chem. Sci.(Engl Transl) (1980) 29, 1830-1833). The protected amine of generalformula (V.viii) thus obtained is then deprotected under standardconditions for a person skilled in the art (for example: trifluoroaceticacid or HCl in an organic solvent when Gp is a protective group ofcarbamate type).

Obtaining the Oxazoles of General Formula (V) Intended for thePreparation of Compounds of General Formula (I)₃:

These compounds are obtained according to a method summarized in Diagram3.5 below. The carboxamide of general formula (VII.ii) is reacted withthe halogenated derivative of general formula (V.vii). The protectedamine of general formula (V.ix) thus obtained is then deprotected understandard conditions for a person skilled in the art in order to producethe compound of general formula (V) (for example: trifluoroacetic acidor HCl in an organic solvent when Gp is a protective group of carbamatetype).

Preparation of the Ketonic Derivatives of General Formula (V.i) and ofCertain α-Bromoketonic Derivatives of General Formula (V.ii), (V.ii)₂ or(V.vii)

The non-commercial ketonic derivatives of general formula (V.i) or theirα-bromoketonic homologues are accessible from methods in the literatureor similar methods adapted by a person skilled in the art. Inparticular:

-   -   when A represents an indolinyl or tetrahydroquinolyl radical,        the compounds of general formula (V.i) are accessible from        methods in the literature such as for example J. Med. Chem.        (1986), 29, (6), 1009-1015 or J. Chem. Soc., Perkin Trans. 1        (1992), 24, 3401-3406;

Alternatively, the compounds of general formula (V.ii) in which Arepresents an indolinyl or tetrahydroquinolyl radical in which R³³represents H can be synthesized according to a protocol which isslightly modified compared to that described in J. Chem. Soc., PerkinTrans 1 (1992), 24, 3401-3406. This protocol is summarized in Diagram3.6 below.

The indoline or tetrahydroquinoline (T represents —CH₂— or —(CH₂)₂—) isprotected using chloroacetyl chloride in order to produce the compoundof general formula (XVII) which is subjected to a Friedel-Craftsreaction (substituted chloroacetyl chloride of general formula (XVIII),in which B has the meaning, indicated previously, in a solvent such ascarbon disulphide and in the presence of aluminium chloride) in order toproduce the compound of general formula (XIX). Then the compound ofgeneral formula (XIX) is hydrolyzed in the presence of acid, for examplean acetic acid/HCl mixture, in order to produce the compounds of generalformula (V.ii) in the form of a mixture of meta and para isomers. Theseisomers can be separated by fractioned crystallization from a solventsuch as glacial acetic acid.

A person skilled in the art will know how to adapt the synthesesdescribed previously to the case where A represents an indolinyl ortetrahydroquinolyl radical in which R³³ does not represent H. Forexample, when R³³ represents an alkyl or aralkyl radical, the protectionand deprotection stages will be unnecessary.

when A represents a radical of 4-(4-hydroxyphenyl)-phenyl type, thecompounds of general formula (V.i) are accessible from methods in theliterature such as for example J. Org. Chem., (1994), 59(16), 4482-4489.

Alternatively, the compounds of general formula (V.i) and (V.ii) inwhich A represents a radical of 4-(4-hydroxyphenyl)-phenyl type areaccessible for example by the method illustrated in Diagram 3.7 below.

The compounds of general formula (V.i) or (V.ii), in which S₁, S₂, S₃and S₄ are chosen independently from a hydrogen atom and OH, cyano,nitro, alkyl, alkoxy or —NR¹⁰R¹¹ as defined in general formula (I), areprepared, Diagram 3.7, from the esters of general formula (XX) (cf. inparticular Chem. Lett. (1998), 9, 931-932 and Synthesis (1993), 8,788-790). Of course, the phenol or aniline functions resulting from thenature of the R¹⁹, R²⁰, R²¹, S₁, S₂, S₃ and S₄ substituents can lead aperson skilled in the art to add to the stages represented in Diagram3.7 protection stages (and, subsequently in the synthesis of thecompounds of general formula (I), deprotection stages) of thesefunctions so that they do not interfere with the remainder of thechemical synthesis. The esters of general formula (XX) are hydrolyzed inorder to produce the acids of general formula (XXI). The latter are thensubjected to coupling with N,O-dimethylhydroxylamine (Syn. Commun.(1995), 25(8), 1255; Tetrahedron Lett. (1999), 40(3), 411-414) in asolvent such as dimethylformamide or dichloromethane, in the presence ofa base such as triethylamine with dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride andhydroxybenzotriazole, in order to produce the intermediates of generalformula (XXII). The compounds of general formula (V.i) are prepared fromthe compounds of general formula (XXII) by a substitution reaction withMeLi (J. Med. Chem. (1992), 35(13), 2392). The bromoacetophenones ofgeneral formula (V.ii) are now accessible from the acetophenone ofgeneral formula (V.i) under the conditions described previously.

when A represents a carbazolyl radical, the compounds of general formula(V.i) are accessible from methods in the literature such as for exampleJ. Org. Chem., (1951), 16, 1198 or Tetrahedron (1980), 36, 3017.

Alternatively, the compounds of general formula (V.ii) in which Arepresents a carbazolyl radical in which R9 represents H can besynthesized according to a protocol which is slightly modified withrespect to that described for A=carbazolyl in Tetrahedron (1980), 36,3017. This method is summarized in Diagram 3.8 hereafter:

The carbazole of general formula (XXIII) is protected using aceticanhydride in order to produce the compound of general formula (XXIV),which is subjected to a Friedel-Crafts reaction (substitutedchloroacetyl chloride of general formula (XVIII) as defined previouslyin a solvent such as carbon disulphide and in the presence of aluminiumchloride) in order to produce the compound of general formula (XXV).

Then the acyl group protecting the amine function is hydrolyzed in thepresence of acid, for example an AcOH/HCl mixture, in order to producethe compound of general formula (V.ii). When A represents a carbazolylradical in which R⁹ represents alkyl or a —COR¹⁵ group (case not shownin Diagram 3.8), the initial acylation stage is unnecessary and the lasttwo stages of Diagram 3.8 allow the compounds of general formula (V.ii)to be obtained. Of course, the phenol or aniline functions resultingfrom the nature of the R⁴, R⁵, R⁶, R⁷ and R⁸ substituents can lead aperson skilled in the art to add to the stages represented in Diagram3.8 protection stages (and, subsequently in the synthesis of thecompounds of general formula (I), deprotection stages) of thesefunctions so that they do not interfere with the remainder of thechemical synthesis.

when A represents a phenothiazinyl radical, the intermediates of generalformula (V.i) and (V.ii) are accessible from methods in the literature:J. Heterocyclic. Chem. (1978), 15, 175-176 and Arzneimittel Forschung(1962), 12, 48.

Alternatively, the intermediates of general formula (V.ii) in which Arepresents a phenothiazinyl radical can be prepared according to aprotocol which is slightly modified with respect to that described forthe phenothiazinyl radical in Arzneimittel Forschung (1962), 12, 48,which is summarized in Diagram 3.9 hereafter (see also the examples).The phenothiazine of general formula (XXVI) is protected usingchloroacetyl chloride in order to produce the compound of generalformula (XXVII), which is then subjected to a Friedel-Crafts reaction(compound of general formula (XVIII) in a solvent such as carbondisulphide in the presence of aluminium chloride) in order to producethe compound of general formula (XXVIII). During the last stage of theprocess, hydrolysis with HCl/acetic acid is accompanied by a halogenexchange and allows the chloroketone of general formula (V.ii) to beobtained. Of course, the phenol or aniline functions resulting from thenature of the R⁴, R⁵, R⁶, R⁷ and R⁸ substituents can lead a personskilled in the art to add to the stages shown in Diagram 3.9 protectionstages (and, subsequently in the synthesis of the compounds of generalformula (I), deprotection stages) of these functions so that they do notinterfere with the remainder of the chemical synthesis.

when A represents a phenylaminophenyl radical, the compounds of generalformula (V.i) are accessible from methods in the literature such as forexample Chem. Commun., (1998), 15, (6) 1509-1510 or Chem Ber., (1986),119, 3165-3197, or similar methods which a person skilled in the artwill have adapted.

For example, the intermediates of general formula (V.i)a and (V.ii)a inwhich A represents a phenylaminophenyl radical (which correspond to thecorresponding compounds of general formula (V.i) and (V.ii) the anilinefunction of which has been acetylated), can be prepared according to aprotocol which is slightly modified with respect to that described forthe phenylaminophenyl radical in Chem Ber. (1986), 119, 3165-3197. Thisprotocol is summarized in Diagram 3.10 hereafter.

In the case (shown in Diagram 3.10) where the R⁹ radical of the compoundof general formula (I) to be synthesized is a hydrogen atom or an acetylgroup, the diphenylamine of general formula (XXIX) formed after thecoupling reaction in the presence of CuI is protected by acetylationusing, for example, acetic anhydride in order to produce the compound ofgeneral formula (V.i)a. In the case (not shown in Diagram 3.10) wherethe R9 radical of the compound of general formula (I) to be synthesizedis not a hydrogen atom or an acetyl radical, the acetylation stave isreplaced by a substitution stage of the aniline according to standardmethods known to a person skilled in the art in order to produce thecorresponding compound of general formula (V.i). The compound of generalformula (V.i)a (or (V.i), in the case not shown in Diagram 3.10) is thensubjected to a bromination reaction using a bromination resin, PVPHPresin (Poly(VinylPyridinium Hydrobromide Perbromide), described in J.Macromol. Sci. Chem. (1977), A11, (3), 507-514, in order to produce thecompound of general formula (V.ii)a (or (V.ii), in the case not shown inDiagram 3.10). Of course, the phenol or aniline functions resulting fromthe nature of the R⁴, R⁵, R⁶, R⁷ and R⁸ substituents can lead a personskilled in the art to add to the stages shown in Diagram 3.10 protectionstages (and, subsequently in the synthesis of the compounds of generalformula (I), deprotection stages) of these functions so that they do notinterfere with the remainder of the chemical synthesis. The deprotectionof the acetylated aniline function will be carried out in principleduring the last stage of the synthesis of the compounds of generalformula (I).when A represents a benzopyran or benzofuran radical as defined ingeneral formula (I) with R³² representing a hydrogen atom, theintermediates of general formula (V.i) and (V.ii) are accessible by themethods illustrated in Diagram 3.11 below.

The compounds of general formulae (V.i) and (V.ii), according to Diagram3.11, in which T is as defined above and Gp=protective group, areprepared from the acids of general formula (XXX). The acids of generalformula (XXX) are subjected to coupling with N,O-dimethylhydroxylamine(Syn. Commun. (1995), 25, (8), 1255; Tetrahedron Lett. (1999), 40, (3),411-414) in a solvent such as dimethylformamide or dichloromethane, inthe presence of a base such as triethylamine withdicyclohexylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride andhydroxybenzotriazol, in order to produce the intermediates of generalformula (XXXI). The protection of the phenol function in the form of abenzylated or tert-butyldimethylsilylated derivative or by otherprotective groups (Gp) known to a person skilled in the art is thencarried out in order to produce the compounds of general formula(XXXII). The compounds of general formula (V.i) are prepared from thecompounds of general formula (XXXII) by a substitution reaction with aGrignard reagent, MeMgCl (J. Het. Chem. (1990), 27, 1709-1712) or withMeLi (J. Med. Chem. (1992), 35, 13). The bromoacetophenones of generalformula (V.ii) are now accessible from the acetophenone of generalformula (V.i) under previously described conditions.

Alternatively, the compound of general formula (V.ii) in which R³²represents a hydrogen atom or an alkyl radical can be prepared accordingto a process in only 3 stages (cf. Diagram 3.12—see also the examples).In this process, the bromination in the last stage of the compound ofgeneral formula (V.i) in order to produce the compound of generalformula (V.ii) will preferably be carried out according to J. Am. Chem.Soc. (1999), 121, 24.

When A represents a substituted phenol radical, it can be necessary touse intermediates of general formula (V.ii) as defined previously thephenol function of which has been acetylated (hereafter designated ascompounds of general formula (V.ii)b). In particular:

-   -   when A represents a 4-hydroxy-3,5-diisopropylphenyl radical, the        homologous α-bromoketonic derivatives of the compound of formula        (V.ii) the phenol function of which is protected by an acetyl        radical can be prepared as summarized in Diagram 3.13 hereafter.

2,6-diisopropylphenol is acetylated according to methods known to aperson skilled in the art, for example by reacting it with acetic acidin the presence of trifluoroacetic acid anhydride or with acetylchloride in the presence of a base such as for example K₂CO₃. Theacetylated homologue of 2,6-diisopropylphenol is then subjected to aFries rearrangement in the presence of aluminium chloride in a solventsuch as nitrobenzene in order to produce the compound of formula (V.i).Then the compound of formula (V.i) is acetylated in order to produce thecompound of formula (V.i)b. Bromination is then carried out with CuBr₂as previously described in order to produce the compound of formula(V.ii)b. The deprotection stage to release the phenol function willoccur subsequently in the synthesis of the compounds of general formula(I) (at the time considered most appropriate by a person skilled in theart).

-   -   when A represents a radical of dimethoxyphenol type, the        compounds of general formula (V.ii)b can be prepared in a        similar fashion to the synthesis described for the compound of        formula (V.ii)b derived from 2,6-diisopropylphenol, optionally        with a few minor modifications within the scope of a person        skilled in the art. For example, when A represents the        3,5-dimethoxy-4-hydroxyphenyl radical, the corresponding        α-bromoketonic derivative of formula (V.ii)b can be prepared,        for example, as indicated in Diagram 3.13 from the commercial        compound of formula (XXXV):

The compounds of general formula (V.ii)₂ in which A and B are as definedpreviously can be prepared according to the method summarized in Diagram3.15 hereafter.

The acids of general formula (XXXVI) are subjected to coupling withN,O-dimethylhydroxylamine (Syn. Commun. (1995), 25, (8), 1255;Tetrahedron Lett. (1999), 40, (3), 411-414) in a solvent such asdimethylformamide or dichloromethane, in the presence of a base such astriethylamine with dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride andhydroxybenzotriazol, in order to produce the intermediates of generalformula (XXXVII). The compounds of general formula (V.i)₂ are preparedfrom the compounds of general formula (XXXVII) by a substitutionreaction with lithium compound or magnesium compound derivatives ofgeneral formula B-M in which M represents Li or MgHal (Hal=I, Br or Cl)in solvents such as ether or anhydrous tetrahydrofuran. The α-bromo- orα-chloroketones of general formula (V.ii)₂ can now be accessed from theketones of general formula (V.i)₂ under the conditions previouslydescribed.

Moreover, the non commercial (X-halogenoketonic derivatives of generalformula (V.vii) are accessible from methods in the literature. Inparticular, they can be obtained according to a procedure summarized inDiagram 3.16.

The protected amino acids of general formula (XXXVIII) are obtained byprotection of the corresponding amino acids by a group of carbamate typeaccording to methods known to a person skilled in the art. The acids ofgeneral formula (XXXVIII) are then subjected to coupling withN,O-dimethylhydroxylamine (Syn. Commun. (1995), 25, (8), 1255;Tetrahedron Lett. (1999), 40, (3), 411-414) in a solvent such asdimethylformamide or dichloromethane, in the presence of a base such astriethylamine with dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride andhydroxybenzotriazole, in order to produce the intermediates of generalformula (XXXIX). The compounds of general formula (XLI) are preparedfrom the compounds of general formula (XXXIX) by a substitution reactionwith lithium compound or magnesium compound derivatives of generalformula (XL) (in which Hal=I, Br or Cl) in solvents such as ether oranhydrous tetrahydrofuran. The bromo or chloroacetophenones of generalformula (V.vii) are now accessible from the acetophenone of generalformula (XLI) under the conditions previously described.

Alternatively, a person skilled in the art can also use or adapt thesyntheses described in Angew. Chem. Int. (1998), 37 (10), 411-414,Liebigs Ann. Chem. (1995), 1217 or Chem. Pharm. Bull. (1981), 29(11),3249-3255.

Preparation of the Acid Derivatives of General Formula (V.iii)

The acid derivatives of general formula (V.iii) can be obtained, Diagram3.17, directly by reaction of the commercial amino acid of generalformula (V.vi) with the compounds of (ar)alkylchloroformate ordi(ar)alkylcarbonate type (Δ represents an alkyl or benzyl radical)under standard conditions known to a person skilled in the art.

Preparations of the Compounds of General Formula (V.v)

The thiocarboxamides of general formula (V.v) can be obtained in threestages starting from the compounds of general formula (V.vi) asindicated in the Diagram 3.18 below. The amine function of the aminoacid of general formula (V.vi) is firstly protected under standardconditions with tBu-O—CO—Cl or (tBu-O—CO)₂O (or other protective groupsknown to a person skilled in the art), then the intermediate obtained isconverted to its corresponding amide by methods described in theliterature (cf. for example, J. Chem. Soc., Perkin Trans. 1, (1998), 20,3479-3484 or the PCT Patent Application WO 99/09829). Finally, thecarboxamide is converted to the thiocarboxamide of general formula(V.v), for example by reaction with Lawesson reagent in a solvent suchas dioxane or tetrahydrofuran at a temperature preferably comprisedbetween ambient temperature and the reflux temperature of the mixture,or also using (P₂S₅)₂ under standard conditions for a person skilled inthe art.

Alternatively, the thiocarboxamides of general formula (V.v) can also beobtained, Diagram 3.19, by the addition of H₂S on the correspondingcyano derivatives of general formula (V.x) under standard conditionsknown to a person skilled in the art.

Preparation of the Acids of General Formula (VI)Preparation of the Acid Derivatives of Thiazoles of General Formula (VI)

The acids of general formula (VI) derived from thiazoles can be preparedaccording to the procedures represented in Diagram 4.1 below.

The carboxamides of general formula (VII.ii) are treated under standardconditions in order to produce the thiocarboxamide of general formula(VII.iii), for example by Lawesson reagent or also using (P₂S₅)₂ understandard conditions for a person skilled in the art. Alternatively theacid of general formula (VII.i) is activated by the action of1,1′-carbonyldiimidazole then treated with methylamine in an aproticpolar solvent such as for example tetrahydrofuran. The carboxamideintermediate obtained is converted to the thiocarboxamide of generalformula (VI.i) under standard conditions, for example using Lawessonreagent or also using (P₂S₅)₂ under standard conditions for a personskilled in the art. The thiocarboxamide of general formula (VII.iii) or(VI.i) is then reacted with the compound of general formula (VI.ii), forexample while heating at reflux in a solvent such as benzene, dioxane ordimethylformamide. The ester of general formula (VI.iii) obtained canthen be saponified by the action of a base such as for example potash inalcoholic medium or LiOH in tetrahydrofuran in order to produce the acidof general formula (VI).

Preparation of the Acid Derivatives of oxazoles of General Formula (VI)

The acids of general formula (VI) derived from oxazoles can be preparedaccording to a procedure represented in Diagram 4.2 below.

The carboxamides of general formula (VII.ii) are reacted with thecompound of general formula (VI.ii) while heating, for example atreflux, in the absence or in the presence of a solvent such asdimethylformamide. The ester of general formula (VI.iv) obtained canthen be saponified by the action of a base such as for example potash inalcoholic medium or LiOH in tetrahydrofuran in order to produce the acidof general formula (VI).

Preparation of the Acid Derivatives of Isoxazolines of General Formula(VI)

The acid derivatives of isoxazolines of general formula (VI), used inthe preparation of compounds of general formula (I)₄, can be preparedaccording to a procedure represented in Diagram 4.3 below.

The acids of general formula (VI) derived from isoxazolines can beprepared as follows: the commercial aldehydes of general formula (VI.v)are reacted with hydroxylamine hydrochloride. The oxime of generalformula (VI.vi) thus obtained is activated in the form of oximechloride, of general formula (VI.vii), by reaction withN-chlorosuccinimide in DMF before reacting with the esters of generalformula (VI.viii) (in which Alk represents an alkyl radical) in order toproduce the isoxazoline derivatives according to an experimentalprotocol described in the literature (Tetrahedron Lett., 1996, 37 (26),4455; J. Med. Chem., 1997, 40, 50-60 and 2064-2084). Saponification ofthe isoxazolines of general formula (VI.ix) is then carried out in astandard fashion (for example by the action of KOH in an alcoholicsolvent or LiOH in a solvent such as tetrahydrofuran) in order toproduce the acid derivative of general formula (VI).

The non-commercial unsaturated esters of general formula (VI.x) can beprepared according to the methods described in the literature (J. Med.Chem., 1987, 30, 193; J. Org. Chem., 1980, 45, 5017).

Preparation of the Thiazoles and Oxazoles of General Formula (VII)

General Outline

The acids of general formula (VII.i), Diagram 5.1, are converted to thecorresponding carboxamides of general formula (VII.ii) by methodsdescribed in the literature (cf. for example, J. Chem. Soc., PerkinTrans. 1, (1998), 20, 3479-3484 or the PCT Patent Application WO99/09829). The compounds of general formula (VII) can then be obtainedin a standard fashion according to the procedures represented inDiagrams 5.2 and 5.3 (thiazoles) and Diagram 5.4 (oxazoles) hereafter.

This synthesis route is useful for then preparing the compoundscorresponding to general sub-formulae (I)₁ and (I)₃.

Obtaining the Thiazoles of General Formula (VII)

When R¹ and R² both represent H, the thiazoles of general formula (VII)intended for the preparation of compounds of general formula (I)₃ can beprepared according to the method summarized in Diagram 5.2. Thecarboxamide of general formula (VII.ii) is converted to thecorresponding thiocarboxamide of general formula (VII.iii) in thepresence of Lawesson reagent in a solvent such as dioxane or benzene ata temperature preferably comprised between ambient temperature and thatof reflux of the mixture. The thiocarboxamide of general formula(VII.iii) is then treated with the α-halogenoketoester of generalformula (VII.iv) in which Alk represents an alkyl radical (for examplemethyl, ethyl or tert-butyl), in order to produce the ester of generalformula (VII.v), which is reduced to the corresponding alcohol ofgeneral formula (VII.vi), for example by the action of lithium aluminiumhydride or diisobutylaluminium hydride in a solvent such astetrahydrofuran. This latter can then be converted to a halogenatedderivative of general formula (VII) according to the methods known to aperson skilled in the art, for example, in the case of a brominatedderivative (L=Br), by reaction with CBr₄ in the presence oftriphenylphosphine in dichloromethane at ambient temperature.

The thiazoles of general formula (VII) intended for the preparation ofcompounds of general formula (I), can be prepared according to themethod summarized in Diagram 5.3. The cyano derivative of generalformula (VII.vii) in which Gp′ is a protective group for an alcoholfunction (for example a benzyl or —CO-ρ group in which ρ representsalkyl, for example methyl or tert-butyl) is converted to thecorresponding thiocarboxamide of general formula (VII.viii) by theaction of H₂S in a solvent such as ethanol in the presence oftriethanolamine at a temperature preferably comprised between ambienttemperature and that of reflux of the mixture. The thiocarboxamide ofgeneral formula (VII.viii) is then treated with the α-halogenoketone ofgeneral formula (VII.ix) in order to produce the compound of generalformula (VII.x), which is deprotected in order to produce thecorresponding alcohol of general formula (VII.xi) according to methodsknown to a person skilled in the art (for example when Gp′ is aprotective group of acetate type, this is removed in situ by the actionof an aqueous solution of sodium carbonate). This latter can then beconverted to a halogenated derivative of general formula (VII) accordingto the methods known to a person skilled in the art, for example, in thecase of a brominated derivative (L=Br), by reaction with CBr₄ in thepresence of triphenylphosphine in dichloromethane at ambienttemperature.

Obtaining the Oxazoles of General Formula (VII)

When R¹ and R² both represent H, the oxazoles of general formula (VII)intended for the preparation of compounds of general formula (I)₃ can beprepared according to the method summarized in Diagram 5.4. Thecarboxamide of general formula (VII.ii) is treated with theα-halogenoketoester of general formula (VII.iv) in which Alk representsan alkyl radical (for example methyl, ethyl or tert-butyl), in order toproduce the ester/acid of general formula (VII.xii). This latter isreduced to the corresponding alcohol of general formula (VII.xiii), forexample by the action of lithium and aluminium hydride ordiisobutylaluminium hydride in a solvent such as tetrahydrofuran whenone starts from the ester or by the action of diborane intetrahydrofuran when one starts from the acid. This latter can then beconverted to a halogenated derivative of general formula (VII) accordingto methods known to a person skilled in the art, for example, in thecase of a brominated derivative (L=Br), by reaction with CBr₄ in thepresence of triphenylphosphine in dichloromethane at ambienttemperature.

Preparation of the Acids of General Formula (VII.i)

The non-commercial acids of general formula (VII.i) are accessible frommethods in the literature. In particular:

when A represents a phenothiazinyl radical, the acids of general formula(VII.i) are accessible from methods in the literature such as forexample J. Med. Chem. (1992), 35, 716-724, J. Med. Chem. (1998), 41,148-156; Synthesis (1988) 215-217; or J. Chem. Soc. Perkin. Trans. 1(1998), 351-354;

when A represents an indolinyl radical, the acids of general formula(VII.i) are accessible from methods in the literature such as forexample J. Het. Chem. (1993), 30, 1133-1136 or Tetrahedron (1967), 23,3823;

when A represents a phenylaminophenyl radical, the acids of generalformula (VII.i) are accessible from methods in the literature such asfor example J. Amer. Chem Soc. (1940), 62, 3208; Zh. Obshch. Khim.(1953), 23, 121-122 or J. Org. Chem. (1974), 1239-1243;

when A represents a carbazolyl radical, the acids of general formula(VII.i) are accessible from methods in the literature such as forexample J. Amer. Chem Soc., (1941), 63, 1553-1555; J. Chem. Soc. (1934),1142-1144; J. Chem. Soc. (1945), 945-956; or Can. J. Chem. Soc. (1982),945-956; and

when A represents a radical of 4-(4-hydroxyphenyl)-phenyl type,reference will be made for example to the following publication:Synthesis (1993) 788-790.

Preparation of the Compounds of General Formula (VIII)

When R¹ and R² both represent H, the protected amino acids of generalformula (VIII) are either commercial, or obtained by protection ofcommercial amino acids by a group of carbamate type according to themethods known to a person skilled in the art.

When at least one of R¹ and R² is not H, and n=0, the protected aminoacids of general formula (VIII) are obtained in one stage, Diagram 6.1,by alkylation, in a solvent such as tetrahydrofuran and at lowtemperature, of commercial compound of general formula (VIII.i) using 3equivalents of butyllithium and approximately one equivalent of thehalogenated derivative of general formula (VIII.ii) in which R¹represents a radical of alkyl, cycloalkyl, cycloalkylalkyl or arylalkyltype and Hal a halogen atom. Depending on the case, a second alkylation(not represented in Diagram 6.1) can be carried out in a similarfashion, thus allowing the compounds of general formula (VIII) to beobtained in which neither R¹ nor R² represents H.

Preparation of the Imidazoles, Thiazoles and Oxazoles of General Formula(IX)

The preparation of the intermediates of general formula (IX) isdescribed in the Patent Application WO 98/58934 (cf. in particular pages10 to 50 and the examples of this document) or carried out by analogyfrom commercial starting products

Preparation of the Protected Alcohols of General Formula (X)

The acid of general formula (X.i) is successively treated, Diagram 8.1,with Cs₂CO₃, the compound of general formula (V.ii) and with NH₄OAc, inorder to produce the compound of general formula (X). The reactionconditions are similar to those described above for this type ofsynthesis.

Preparation of the Compounds of General Formula (X) Derived fromThiazoles

The cyano derivative of general formula (X.ii) is treated, Diagram 8.2,with H₂S in order to produce the thiocarboxamide of general formula(X.iii), which, condensed with the compound of general formula (V.ii),allows the compound of general formula (X) to be obtained. The reactionconditions are similar to those described above (Diagram 5.3) for thistype of synthesis.

Preparation of the Acids of General Formula (XXXVI)

The non commercial acids of general formula (XXXVI) are accessible frommethods in the literature or similar methods adapted by a person skilledin the art. In particular:

-   -   when A represents a phenothiazinyl radical, the acids of general        formula (XXXVI) are accessible from methods in the        literature: J. Org. Chem., (1956), 21, 1006; Chem. Abstr., 89,        180029 and Arzneimittel Forschung (1969), 19, 1193.    -   when A represents a diphenylamine radical, the acids of general        formula (XXXVI) can be accessed from methods in the literature:        Chem Ber., (1986), 119, 3165-3197; J. Heterocyclic. Chem.        (1982), 15, 1557-1559; Chem. Abstr., (1968), 68, 68730x; or by        adaptation of these methods by a person skilled in the art;    -   when A represents a radical of 4-(4-hydroxyphenyl)-phenyl type,        the acids of general formula (XXXVI) can be accessed from        methods in the literature such as for example Tetrahedron Lett.        (1968), 4739 or J. Chem. Soc. (1961), 2898.    -   when A represents a carbazolyl radical, the acids of general        formula (XXXVI) can be accessed from methods in the literature        such as for example J. Amer. Chem., (1946), 68, 2104 or J. Het.        Chem (1975), 12, 547-549.    -   when A represents a radical of benzopyrane or benzofurane type,        the acids of general formula (XXXVI) can be accessed by the        methods in the literature such as for example Syn. Commun.        (1982), 12(8), 57-66; J. Med. Chem. (1995), 38(15), 2880-2886;        or Helv. Chim. Acta. (1978), 61, 837-843.    -   when A represents an indolinyl or tetrahydroquinolyl radical,        the acids of general formula (XXXVI) can be accessed from        methods in the literature such as for example J. Med. Chem.        (1997), 40, (7), 1049-1062; Bioorg. Med. Chem. Lett. (1997),        1519-1524; Chem. Abstr. (1968), 69, 43814k; or Chem. Abstr.        (1966), 66, 17538c.

Of course, the phenol, amine or aniline functions resulting from thenature of the substituents on the A radical of the compounds of generalformula (XXXVI) can lead a person skilled in the art to addprotection/deprotection stages of these functions to the stagesdescribed so that they do not interfere with the rest of the chemicalsynthesis.

Unless defined otherwise, all the technical and scientific terms usedhere have the same meaning as that usually understood by an ordinaryspecialist in the field to which this invention belongs. Likewise, allpublications, patent applications, all patents and all other referencesmentioned here are incorporated by way of reference.

The following examples are presented to illustrate the above proceduresand must in no case be considered as limiting the scope of theinvention.

EXAMPLES Example 14-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-2-thiazolemethanamine

This product is obtained according to the procedure described in the PCTPatent Application WO 98/58934. Alternatively, it can also be preparedaccording to the method described below.

1.1) N—Boc-sarcosinamide

15.0 g (0.120 mol) of sarcosinamide hydrochloride (N-Me-Gly-NH₂.HCl) isdissolved in dichloromethane containing 46.2 ml (0.265 mol) ofdiisopropylethylamine. The mixture is cooled down to 0° C. thenBoc—O—Boc (28.8 g; 0.132 mol) is added in fractions and the mixture isstirred overnight at ambient temperature. The reaction medium is thenpoured into ice-cooled water followed by extraction withdichloromethane. The organic phase is washed successively with a 10%aqueous solution of sodium bicarbonate and with water, then finally witha saturated solution of sodium chloride. The organic phase is then driedover magnesium sulphate, filtered and concentrated under vacuum. Theproduct obtained is purified by crystallization from diisopropyl etherin order to produce a white solid with a yield of 72%. Melting point:103° C.

1.2) 2-{[(1,1-dimethylethoxy)carbonyl]methyl}amino-ethanethioamide

16.0 g (0.085 mol) of intermediate 1.1 is dissolved in dimethoxyethane(500 ml) and the solution obtained is cooled down to 5° C. Sodiumbicarbonate (28.5 g; 0.34 mol) then, in small portions, (P₂S₅)₂ (38.76g; 0.17 mol) are added. The reaction medium is allowed to return toambient temperature under stirring over 24 hours. After evaporation ofthe solvents under vacuum, a 10% aqueous solution of sodium bicarbonateis added to the residue and the solution is extracted using ethylacetate. The organic phase is washed successively with a 10% aqueoussolution of sodium bicarbonate and with water, then finally with asaturated solution of sodium chloride. The organic phase is then driedover magnesium sulphate, filtered and concentrated under vacuum. Theproduct obtained is purified by crystallization from ether in order toproduce a white solid with a yield of 65%. Melting point: 150-151° C.

1.3)4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-[(1,1-dimethylethoxy)-carbonyl]-N-methyl-2-thiazolemethanamine

Intermediate 1.2 (4.3 g; 2.11 mmol) andbromo-1-(3,5-ditert-butyl-4-hydroxyphenyl)ethanone (6.9 g; 2,11 mmol)are dissolved in benzene (75 ml) under an argon atmosphere, then themixture is stirred at ambient temperature for 12 hours. The reactionmedium is heated under reflux for 4 hours. After evaporation of thesolvents, the residue is diluted with dichloromethane and washed with asaturated solution of NaCl. The organic phase is separated, dried overmagnesium sulphate, filtered and concentrated under vacuum. The expectedproduct is obtained after chromatography on a silica column (eluent: 20%ethyl acetate in heptane) in the form of an oil which crystallizes veryslowly in a refrigerator with a yield of 28%. Melting point:126.5-127.3° C.

1.4)4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-2-thiazolemethanamine

2.3 ml (29 mmol) of trifluoroacetic acid is added dropwise, at 0° C. toa solution of 2.5 g (5.8 mmol) of intermediate 1.3 and 2 ml (1.6 mmol)of triethylsilane in 50 ml of dichloromethane. After stirring for onehour, the reaction mixture is concentrated under vacuum and the residueis diluted in 100 ml of ethyl acetate and 50 ml of a saturated solutionof NaHCO₃. After stirring and decantation, the organic phase is driedover magnesium sulphate, filtered and concentrated under vacuum. Theresidue is taken up in heptane in order to produce, after drying, awhite solid with a yield of 73%. Melting point: 136° C.

1.54-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-2-thiazolemethanaminehydrochloride

2.0 g (0.602 mmol) of intermediate 1.4 is dissolved in anhydrous ether.The solution is cooled down to 0° C. then 18 ml (1.81 mmol) of a 1Nsolution of HCl in ether is added dropwise. The mixture is allowed toreturn to ambient temperature under stirring. After filtering and dryingunder vacuum, a white solid is obtained with a yield of 92%. Meltingpoint: 185.3-186.0° C.

Example 22,6-di(tert-butyl)-4-(2-{[methyl(2-propynyl)amino]methyl}-1,3-thiazol-4-yl)phenol

0.52 ml (3.7 mmol) of triethylamine and an excess of 0.56 g (7.5 mmol)of chloropropargyl are added dropwise at 0° C. to a solution of 0.5 g(1.5 mmol) of the compound of Example 1 in 15 ml of acetonitrile. Afterstirring overnight, the reaction mixture is concentrated under vacuumand the residue is diluted with dichloromethane and 50 ml of a saturatedsolution of NaCl. After stirring and decantation, the organic phase isseparated and dried over magnesium sulphate, filtered and concentratedunder vacuum. The expected product is obtained after chromatography on asilica column (eluent: 20% ethyl acetate in heptane). After evaporation,the pure fractions produce a white solid with a yield of 20%. Meltingpoint: 210-215° C.

MH+=371.20.

Example 32-[({4-[3,5-di(tert-butyl)-4-hydroxyphenyl]-1,3-thiazol-2-yl}methyl)(methyl)amino]acetonitrile

The experimental protocol used is identical to that described forExample 2, chloroacetonitrile being used as starting product in place ofthe chloropropargyl. A beige solid is obtained with a yield of 54%.Melting point: 150-156° C.

MH+=372.30

Example 45-[({4-[3,5-di(tert-butyl)-4-hydroxyphenyl]-1,3-thiazol-2-yl}methyl)(methyl)amino]pentanenitrile

The experimental protocol used is identical to that described forExample 2, bromovaleronitrile being used as starting product in place ofthe chloropropargyl. A yellow oil is obtained with a yield of 24%.

MH+=414.30

Example 56-[({4-[3,5-di(tert-butyl)-4-hydroxyphenyl]-1,3-thiazol-2-yl}methyl)(methyl)amino]hexanenitrile

The experimental protocol used is identical to that described forExample 2, bromohexanenitrile being used as starting product in place ofthe chloropropargyl. A red oil is obtained with a yield of 35%.

MH+=428.40.

Example 62,6-di(tert-butyl)-4-(2-{[(2-hydroxyethyl)(methyl)amino]methyl}-1,3-thiazol-4-yl)phenol

The experimental protocol used is identical to that described forExample 2, 2-bromoethanol is used as starting product in place of thechloropropargyl. A yellow oil is obtained with a yield of 57%.

MH+=377.30

Example 74-(2-{[benzyl(methyl)amino]methyl}-1,3-thiazol-4-yl)-2,6-di(tert-butyl)phenol

The experimental protocol used is identical to that described forExample 2, benzyl chloride being used as starting product in place ofthe chloropropargyl. A white solid is obtained with a yield of 52%.Melting point: 165-170° C.

MH+=423.30

Example 82,6-di(tert-butyl)-4-{2-[(methyl-4-nitroanilino)methyl]-1,3-thiazol-4-yl}phenol

This product is obtained according to the procedure described in the PCTPatent Application WO 98/58934.

Example 92,6-di(tert-butyl)-4-(2-{[4-(dimethylamino)(methyl)anilino]methyl}-1,3-thiazol-4-yl)phenol

0.8 ml of paraformaldehyde and 0.10 g of 20% palladium on carbon isadded to a solution of 0.5 g (1.1 mmol) of Example 8 in 20 ml ofethanol. The medium is placed under hydrogen for 4 hours. The catalystis filtered out and the solvent evaporated to dryness. The expectedproduct is obtained after chromatography on a silica column (eluent: 3%ethanol in dichloromethane). The expected compound is obtained in theform of a brown oil with a yield of 54%.

MH+=452.30

Example 10benzyl{4-[3,5-di(tert-butyl)-4-hydroxyphenyl]-1,3-thiazol-2-yl}methylcarbamate

The compound is produced according to an experimental protocol describedin the Patent Application WO 98/58934 (see preparation of intermediates26.1 and 26.2), using Z-Gly-NH₂ in place of the N—Boc sarcosinamide. Theexpected compound is obtained in the form of a pale yellow oil with ayield of 99%.

MH+=453.20

Example 11 4-[2-(aminomethyl)-1,3-thiazol-4-yl]-2,6-di(tert-butyl)phenol

0.1 ml of a 40% solution of potassium hydroxide is added dropwise to asolution of 0.106 g (1.1 mmol) of the compound of Example 10 in 10 ml ofmethanol. After overnight stirring under reflux, the reaction mixture isconcentrated under vacuum and the residue is diluted withdichloromethane and washed with a 1N solution of HCl then with 50 ml ofa saturated solution of NaCl. The organic phase is separated and driedover magnesium sulphate, filtered and concentrated under vacuum. Theexpected product is obtained after chromatography on a silica column(eluent: 5% ethanol in dichloromethane) in the form of a brown foam witha yield of 76%.

MH+=319.29.

Example 122,6-di(tert-butyl)-4-(2-{[methyl(4-nitrobenzyl)amino]methyl}-1,3-thiazol-4-yl)phenol

The experimental protocol used is identical to that described forExample 2, 4-nitro-benzyl bromide being used as starting product inplace of the chloropropargyl. A yellow solid is obtained with a yield of63%. Melting point: 114.4-111.7° C.

MH+=468.3

Example 134-(2-{[(4-aminobenzyl)(methyl)amino]methyl}-1,3-thiazol-4-yl)-2,6-di(tert-butyl)phenol

0.059 g (0.26 mmol) of SnCl_(2,) 2H₂O and 0.017 g (0.26 mmol) of Zn areadded successively to a solution of 0.05 g (0.107 mmol) of the compoundof Example 12 in a mixture of 0.55 ml of glacial acetic acid and 0.07 mlof a 12N solution of HCl. The mixture is stirred for 18 hours at 20° C.The reaction mixture is then made basic by adding a 30% aqueous solutionof NaOH. The product is then extracted using two times 50 ml of CH₂Cl₂.The organic solution is washed with 50 ml of salt water, dried overMgSO₄, filtered and concentrated under vacuum. The residue is purifiedon a silica column (eluent: 5% ethanol in dichloromethane). A yellow gumis obtained with a yield of 52%.

MH+=438.29.

Example 142,6-di(tert-butyl)-4-(2-{[(4-nitrobenzyl)amino]methyl}-1,3-thiazol-4-yl)phenol

0.5 g (1.57 mmol) of the compound of Example 9, 0.237 g (1.57 mmol) of4-nitrobenzaldehyde and 1 g of previously activated pulverulent 4 Åmolecular sieve are added successively to a flask containing 30 ml ofanhydrous MeOH, under an inert atmosphere. The reaction mixture isvigorously stirred for 18 hours before the addition, by portions, of0.06 g (1.57 mmol) of NaBH₄. Stirring is maintained for another 4 hoursbefore the addition of 5 ml of water. After a quarter of hour, the sieveis filtered out and the reaction mixture is extracted with two times 100ml of CH₂Cl₂. The organic phase is washed successively with 50 ml ofwater then with 50 ml of salt water, dried over sodium sulphate,filtered and concentrated under vacuum. The residue is purified on asilica column (eluent: 50% ethyl acetate in heptane). A yellow oil isobtained with a yield of 55%.

MH+=454.20.

Example 154-(2-{[(4-aminobenzyl)amino]methyl}-1,3-thiazol-4-yl)-2,6-di(tert-butyl)phenol

The experimental protocol used is identical to that described forExample 13, the compound of Example 14 being used as starting product inplace of the compound of Example 12. A yellow gum is obtained with ayield of 83%.

MH+=424.20.

The Compounds of the examples 16 to 22 can be obtained according to theprocedures described in the PCT Patent Applications WO 98/58934.

Example 164-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-N-(4-aminophenyl)-2-thiazolemethanamine

[is intermediate 26.5 of the PCT Application WO 98/58934]

Example 174-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-1H-imidazole-2-methanamine

Intermediate 26.2 of the PCT Application WO 98/58934 is subjected to ahydrogenation as described in Stage 1.2 of the same document usingethanol as reaction solvent in place of methanol. The expected productis isolated in the form of a red foam.

MH+=316.33.

Example 184-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-N-(4-nitrophenyl)-1H-imidazole-2-methanamine

[is intermediate 27.2 of the PCT Application WO 98/58934]

Example 194-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-N-(4-aminophenyl)-1H-imidazole-2-methanamine

[is intermediate 27.3 of the PCT Application WO 98/58934]

Example 204-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-N-(4-nitrobenzoyl)-1H-imidazole-2-methanamine

[is intermediate 22.6 of the PCT Application WO 98/58934]

Example 214-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-N-(4-aminobenzoyl)-1H-imidazole-2-methanamine

[is intermediate 22.7 of the PCT Application WO 98/58934]

Example 223-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-5-isoxazoleethanol

[is intermediate 28.1 of the PCT Application WO 98/58934]

The compound of Example 23 can be obtained according to the proceduresdescribed in the PCT Patent Application WO 99/09829.

Example 232-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4-oxazoleethanol

[is intermediate 1.C of the PCT Application WO 99/09829; alternatively,this compound can also be obtained according to the procedure describedin J. Med. Chem. (1996), 39, 237-245.]

Example 244-[{[4-(3,5-ditert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}(methyl)amino]butanenitrile

The experimental protocol used is identical to that described forExample 2, bromobutyronitrile being used as starting product in place ofthe chloropropargyl. A yellow oil is obtained with a yield of 18%.

MH⁺=400.30.

Example 252,6-ditert-butyl-4-(2-{[(3-nitrobenzyl)amino]methyl}-1,3-thiazol-4-yl)phenol

The experimental protocol used is identical to that described forExample 14, 3-nitrobenzaldehyde being used as starting product in placeof the 4-nitrobenzaldehyde. A yellow oil is obtained with a yield of28%.

MH+=454.20.

Example 262,6-ditert-butyl-4-(4-{2-[methyl(2-propynyl)amino]ethyl)-1,3-oxazol-2-yl)phenol

The compound of Example 23 is converted to brominated derivative,intermediate 3, according to the procedure indicated in Diagram 1(c) ofthe PCT Application WO 99/09829. Then the brominated derivative (0.5 g;1.31 mmol) is added to a solution of N-methylpropargylamine 0.34 ml(3.94 mmol) and potassium carbonate (1.11 g) in dimethylformamide (20ml). After overnight stirring at 80° C., the reaction mixture isconcentrated under vacuum and the residue is diluted withdichloromethane and 50 ml of a saturated solution of NaCl. Afterstirring and decantation, the organic phase is separated and dried overmagnesium sulphate, filtered and concentrated under vacuum. The expectedproduct is obtained after chromatography on a silica column (eluent: 50%ethyl acetate in heptane). After evaporation, the pure fractions producea yellow oil with a yield of 24%.

MH+=369.30.

Example 27[{2-[2-(3,5-ditert-butyl-4-hydroxyphenyl)-1,3-oxazol-4-yl]ethyl}(methyl)amino]acetonitrile

The experimental protocol used is identical to that described for thecompound of Example 26, methylaminoacetonitrile being used as startingproduct in place of the N-methylpropargylamine. A white solid isobtained with a yield of 36%. Melting point: 165-167.8° C.

Example 283-[{2-[2-(3,5-ditert-butyl-4-hydroxyphenyl)-1,3-oxazol-4-yl]ethyl}(methyl)amino]propanenitrile

The experimental protocol used is identical to that described forExample 26, N-methyl-β-alaninenitrile being used as starting product inplace of the N-methylpropargylamine. A white solid is obtained with ayield of 56%. Melting point: 104-104.8° C.

Example 292,6-ditert-butyl-4-{4-[2-(1-piperazinyl)ethyl]-1,3-oxazol-2-yl}phenolhydrochloride 29.1) tert-butyl4-{[2-[2-(3,5-ditert-butyl-4-hydroxyphenyl)-1,3-oxazol-4-yl]ethyl}-1-piperazinecarboxylate

The experimental protocol used is identical to that described forExample 26, tert-butyl piperazinecarboxylate being used as startingproduct in place of the N-methylpropargylamine. A brown oil is obtainedwith a yield of 72%.

MH+=486.20.

29.2)2,6-ditert-butyl-4-(4-[2-(1-piperazinyl)ethyl]-1,3-oxazol-2-yl]phenolhydrochloride

A stream of HCl gas is passed bubblewise into a solution at 0° C. ofintermediate 29.1 (0.450 g; 9.27 mmol) in ethyl acetate (30 ml). Themixture is left to return to ambient temperature overnight. A stream ofargon is passed through the reaction mass, then the powder obtained isfiltered and washed with ethyl acetate then with ether in order toproduce a white solid with a yield of 70%. Melting point: >200° C.

Example 30N-methyl[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]methanaminehydrochloride

The experimental protocol used is identical to that described forExample 1,2-bromo-1-(10H-phenothiazin-2-yl)ethanone (J. Heterocyclic.Chem., (1978), 15, 175-176 and Arzneimittel Forschung, (1962), 12, 48),being used as starting product in place of the2-bromo-1-(3,5-ditert-butyl-4-hydroxyphenyl)ethanone. The productobtained is purified by recrystallization from glacial acetic acid inorder to produce a greenish solid. Melting point: >275° C.

Alternatively, this compound can be obtained according to a similarmethod, but using 2-chloro-1-(10H-phenothiazin-2-yl)ethanone instead of2-bromo-1-(10H-phenothiazin-2-yl)ethanone:

30.1) 2-chloro-1-(10H-phenothiazin-2-yl)ethanone

2-bromo-1-[10-(chloroacetyl)-10H-phenothiazin-2-yl)ethanone (2.2 g; 5.55mmol; prepared according to a protocol described in J. Heterocyclic.Chem. (1978), 15, 175, followed by a Friedel-Crafts reaction) isdissolved hot in a mixture of acetic acid (20 ml) and 20% HCl (5.5 ml)and the mixture obtained is heated under reflux for 30 minutes. Thereaction mixture is allowed to cool down, the precipitate is filtered,the mixture rinsed with acetic acid (5 ml) and dried under vacuum, thesolid obtained is purified by crystallization from toluene in order toproduce a brown product with a yield of 82%. Melting point: 190-191° C.(value in the literature: 197-198° C.).

30.2) N-methyl[4-(10H-phenothiazin-2-yl)-1,3-thiazol-2-yl]methanaminehydrochloride

Intermediate 30.1 (0.280 g; 1.0 mmol) and tert-butyl2-amino-2-thioxoethyl(methyl)carbamate (0.204 g; 1.0 mmol; described forexample in PCT Patent Application WO 98/58934) are dissolved in tolueneand the mixture is heated under reflux for 18 hours. After the tolueneis evaporated off and the reaction mixture cooled down to 0° C., thelatter is taken up in a 4N solution of HCl in dioxane (10 ml) and themixture stirred for one hour at 0° C. before allowing the temperature toreturn to ambient temperature. The solid formed is filtered and rinsedwith ether. The expected product is obtained after purification bycrystallization from hot acetic acid in order to obtain a greenishsolid. Melting point: >275° C.

Example 31 butyl2-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)ethylcarbamate 31.1)N-(butoxycarbonyl)-β-alanine

A solution containing β-alanine (8.9 g; 0.1 mol) and 100 ml of a 1Nsolution of sodium hydroxide is cooled down to 10° C. n-butylchloroformate (13.66 g; 0.1 mol) and 50 ml of a 2N solution of sodiumhydroxide are added simultaneously. After stirring for 16 hours at 23°C., approximately 10 ml of a solution of concentrated hydrochloric acid(approximately 11 N) is added in order to adjust the pH to 4-5. The oilobtained is extracted with ethyl acetate (2×50 ml), washed with waterthen dried over magnesium sulphate. The product crystallizes fromisopentane in the form of a white powder (yield of 68%). Melting point:50.5° C.

31.2) butyl 2-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)ethylcarbamate

A mixture of N-(butoxycarbonyl)-β-alanine (prepared in Stage 31.1; 5.67g; 0.03 mol) and caesium carbonate (4.89 g; 0.015 mol) in 100 ml ofethanol is stirred at 23° C. for 1 hour. The ethanol is eliminated byevaporation under reduced pressure in a rotary evaporator. The mixtureobtained is dissolved in 100 ml of dimethylformamide then4-phenyl-bromoacetophenone (8.26 g; 0.03 mol) is added. After stirringfor 16 hours, the solvent is evaporated off under reduced pressure. Themixture obtained is taken up in ethyl acetate then the caesium bromideis filtered. The ethyl acetate of the filtrate is evaporated and thereaction oil is taken up in a mixture of xylene (100 ml) and ammoniumacetate (46.2 g; 0.6 mol). The reaction medium is heated at reflux forapproximately one hour and 30 minutes then, after cooling down, amixture of ice-cooled water and ethyl acetate is poured into thereaction medium. After decantation, the organic phase is washed with asaturated solution of sodium bicarbonate, dried over magnesium sulphatethen evaporated under vacuum. The solid obtained is filtered then washedwith ether in order to produce a light beige-coloured powder (yield of50%). Melting point: 136.7° C.

MH+=364.3.

Example 32N-[2-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)ethyl]pentanamide 32.1)tert-butyl 2-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)ethylcarbamate

This compound is obtained according to an operating method similar tothat of Stage 31.2 of Example 31, N-(tert-butoxycarbonyl)-β-alanine acidreplacing the β-alanine. A yellow-coloured powder is obtained with ayield of 37%.

MH+=364).

32.2) 2-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)ethylamine

tert-butyl 2-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)ethylcarbamate(4.8 g; 0.013 mol) is stirred in 120 ml of a solution of ethyl acetatesaturated in hydrochloric acid for 2 hours 30 minutes at a temperatureof 55° C. The solid obtained is filtered and washed with ether. A lightbeige-coloured powder is obtained with a yield of 89%.

MH+=264.2.

32.3) N-[2-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)ethyl]pentanamide

A mixture containing valeric acid (0.24 ml; 0.002 mol),dicyclohexylcarbodiimide (2.2 ml; 1M solution in methylene chloride) and1-hydroxybenzotriazole hydrate (336 mg; 0.0022 mol) in 15 ml ofdimethylformamide (DMF) is stirred at 23° C. for thirty minutes. The2-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)ethylamine preparedpreviously is added then the mixture is stirred for 48 hours at 23° C.The dicyclohexylurea formed is filtered then the DMF is evaporated offunder reduced pressure. The residue obtained is taken up in ethylacetate then the residual dicyclohexylurea is filtered again. Thefiltrate is washed with water and extracted using ethyl acetate. Thesolvent is evaporated off then purification is carried out on a silicacolumn (eluent: CH₂Cl₂-MeOH/95-05). A white-coloured powder is obtainedwith a yield of 13%. Melting point: 166-167° C.

MH+=348.2.

Example 33N-[2-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)ethyl]-1-butanesulphonamide

A mixture containing2-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)ethylamine (obtained in Stage32.2 of Example 32; 660 mg; 0.0025 mol) and n-butane sulphochloride (390mg; 0.0025 mol) in 20 ml of DMF is stirred for two hours at 23° C.Potassium carbonate (345 mg; 0.0025 mol.) is then added, then stirringis continued for two hours. The solvent is evaporated off and thereaction mixture is taken up in water and dichloromethane. The organicphase is washed with a saturated solution of sodium chloride then dried.The solvent is evaporated off and the residue obtained is purified on asilica column (eluent: CH₂Cl₂-MeOH/93-07). A light beige-coloured powderis obtained with a yield of 19%. Melting point: 168.5° C.

MH+=384.2.

Example 344-[2-(2-{[butylamino)carbonyl]amino}ethyl)-1H-imidazol-4-yl]-1,1′-biphenyl

A mixture containing2-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)ethylamine (obtained in Stage32.2 of Example 32; 660 mg; 0.0025 mol) and n-butyl isocyanate (341 mg;0.0025 mol) in 20 ml of 1,2-dichloroethane is stirred for fifteenminutes at 60° C. The suspension is stirred for sixteen hours at 23° C.and filtered. The solid obtained is washed with 1,2-dichloroethane andwith ether. A white-coloured powder is obtained with a yield of 66%.Melting point: 178° C.

MH+=363.3.

Example 35N-{(S)-cyclohexyl[4-(4-fluorophenyl)-1H-imidazol-2-yl]methyl}cyclobutanamine35.1 tert-butyl)(S)-cyclohexyl[4-(4-fluorophenyl)-1H-imidazol-2-yl]methylcarbamate

This compound is obtained according to an operating method similar tothe preparation of the compound of Stage 31.2 of Example 31 usingBoc-aminocyclohexylglycine (9.4 g; 0.036 mol) in place of theN-(butoxycarbonyl)-β-alanine and parafluorobromoacetophenone (7.9 g;0.036 mol) in place of the 4-phenyl-bromoacetophenone. A white-colouredpowder is obtained with a yield of 53%.

MH+=374.2.

35.2) (S)-cyclohexyl[4-(4-fluorophenyl)-1H-imidazol-2-yl]methanamine

This compound is prepared according to an operating method similar tothat of Stage 32.2 of Example 32 usingtert-butyl(S)-cyclohexyl[4-(4-fluorophenyl)-1H-imidazol-2-yl]methylcarbamate(7.5 g; 0.02 mol) as starting compound. A white-coloured powder isobtained with a yield of 92%.

MH+=274.2.

35.3)N-{(S)-cyclohexyl[4-(4-fluorophenyl)-1H-imidazol-2-yl]methyl}cyclobutanamine

A mixture containing(S)-cyclohexyl[4-(4-fluorophenyl)-1H-imidazol-2-yl]methanamine (preparedin Stage 5.2; 519 mg; 0.0015 mol), triethylamine (0.4 ml; 0.003 mol) andbutanone (140 mg; 0.002 mol) in 10 ml of methanol is stirred for thirtyminutes at 23° C. Sodium triacetoxyborohydride (630 mg; 0.003 mol) isthen added. The reaction mixture is stirred for sixteen hours thenpoured into water. After extraction with ethyl acetate, the organicphase is washed with a saturated solution of sodium chloride then driedover magnesium sulphate. The solvent is evaporated off and the residueis purified on a silica column (eluent: CH₂Cl₂-MeOH mixture/95-05). Awhite-coloured powder is obtained with a yield of 12%. Melting point:170-172° C.

MH+=328.2.

Example 36 N-[1-(4-cyclohexyl-1H-imidazol-2-yl)heptyl]cyclohexanamine36.1) 2-bromo-1-cyclohexylethanone

Cyclohexylacetone (5.4 ml, 0.039 mol) and bromine (2 ml, 0.039 mol) arestirred at 23° C. in 100 ml of methanol. After decolourization, 100 mlof water are gently added. The mixture obtained is neutralized with 5 gof sodium bicarbonate. Extraction is carried out with ether followed bywashing the organic phase with 100 ml of water. After drying overmagnesium sulphate, the mixture is concentrated with a rotaryevaporator. An oil is obtained with a yield of 97% c.

NMR ¹H (δ ppm, DMSO): 1.21-1.27 (m, 5H); 1.59-1.83 (m, 5H); 2.59-2.64(m, 1H); 4.42 (s, 2H).

36.2) 2-[(tert-butoxycarbonyl)amino]octanoic acid

A mixture of 2-amino-octanoic acid (25.25 g; 0.156 mol) anddi-tert-butyl dicarbonate (37.8 g; 0.173 mol) in 425 ml of dioxane isstirred at reflux for three hours. After returning to 23° C., themixture is again stirred for twenty four hours then the insoluble partis filtered out. The filtrate is evaporated. An oil is obtained with ayield of 99%. NMR H¹ (δ ppm, DMSO): 0.85 (t, 3H); 1.11-1.27 (m, 8H);1.37 (s, 9H); 1.51-1.65 (m, 2H); 3.81-3.87 (m, 1H); 6.96-6.97 (m, 1H);12.3 (s, 1H).

IR (cm⁻¹): 3500; 2860; 1721 (ν_(C═O) (acid)); 1680 (ν_(C═O)(carbamate)); 1513 (ν_(C—NH) (carbamate)).

36.3) tert-butyl 1-(4-cyclohexyl-1H-imidazol-2-yl)heptylcarbamate

This compound is obtained according to an operating method similar tothat of Stage 31.2 of Example 31, using2-[(tert-butoxycarbonyl)amino]octanoic acid (8.1 g; 0.0314 mol) in placeof the N-(butoxycarbonyl)-β-alanine and 2-bromo-1-cyclohexylethanone(6.4 g; 0.0314 mol) in place of the 4-phenyl-bromoacetophenone. An oilis obtained which is sufficiently pure to be used in the followingreaction (yield of 88%).

36.4) 1-(4-cyclohexyl-1H-imidazol-2-yl)-1-heptanamine

This compound is obtained according to an operating method similar tothat of Stage 32.2 of Example 32 using as starting compound tert-butyl1-(4-cyclohexyl-1H-imidazol-2-yl)heptylcarbamate (prepared in Stage 6.3;10 g; 0.0275 mol). A yellow solid is obtained in the form of a paste(yield of 37%).

MH+=264.2

36.5) N-[1-(4-cyclohexyl-1H-imidazol-2-yl)heptyl]cyclohexanamine

This compound is obtained according to an operating method similar tothat of Stage 35.3 of Example 35 using as starting amine1-(4-cyclohexyl-1H-imidazol-2-yl)-1-heptanamine (obtained in Stage 6.4;2.5 g; 0.074 mol) and as ketone, cyclohexanone (1 ml; 0.0097 mol). Afterpurification on a silica column (eluent: ethyl acetate—heptane/7-3 withCH₂Cl₂-MeOH/95-05), a white-coloured powder is obtained with a yield of12%. Melting point: 172-174° C.

MH+=346.3.

Example 37N-{1-[4-(3-bromophenyl)-1H-imidazol-2-yl]-5-methylhexyl}-N-cyclohexylamine37.1) 2-[(tert-butoxycarbonyl)amino]-6-methylheptanoic acid

A solution of diisopropylamine (13.2 ml; 0.094 mol) in 130 ml oftetrahydrofuran (THF) is cooled down to −40° C. n-butyllithium (37 ml ofa 2.5 M solution in hexane; 0.094 mol) is added dropwise. Thetemperature is allowed to rise to 0° C. At this temperature, Boc-glycine(5 g; 0.028 mol) in solution in 30 ml of THF is introduced into themixture. The reaction medium is left for ten minutes at this temperaturethen 1-bromo-4-methylpentane (7.9 ml; 0.056 mol) in solution in 20 ml ofTHF is added rapidly. The temperature is allowed to return to 23° C. andthe mixture is stirred at this temperature for one hour. Afterhydrolysis with 100 ml of water then acidification with 150 ml of asaturated solution of potassium hydrogen sulphate, the mixture obtainedis extracted twice with 50 ml of ethyl acetate. The organic phase iswashed with 100 ml of water then with 100 ml of a saturated solution ofsodium chloride. After drying over magnesium sulphate and evaporatingthe solvent, the residue obtained is purified on a silica column(eluent: ethyl acetate—heptane/6-4) in order to produce a white-colouredpowder with a yield of 50%.

MH+=260.3.

37.2) tert-butyl1-[4-(3-bromophenyl)-1H-imidazol-2-yl]-5-methylhexylcarbamate

This compound is obtained according to an operating method similar tothat of Stage 31.2 of Example 31 using2-[(tert-butoxycarbonyl)amino]-6-methylheptanoic acid (3.5 g; 0.0135mol) in place of the N-(butoxycarbonyl)-β-alanine and 3-bromophenacylbromide (3.75 g; 0.0135 mol) in place of the 4-phenyl-bromoacetophenone.A white powder is obtained with a yield of 63%. Melting point: 134-136°C.

MH+=436.2.

37.3) 1-[4-(3-bromophenyl)-1H-imidazol-2-yl]-5-methyl-1-hexanamine

This compound is obtained according to an operating method similar tothat of Stage 32.2 of Example 32 using as starting compound tert-butyl1-[4-(3-bromophenyl)-1H-imidazol-2-yl]-5-methylhexylcarbamate (obtainedin Stage 37.2; 3.5 g; 0.008 mol). A white-coloured powder is obtainedwith a yield of 97%. Melting point: 200-202° C.

MH+=336.2.

37.4)N-{1-[4-(3-bromophenyl)-1H-imidazol-2-yl]-5-methylhexyl}-N-cyclohexylamine

This compound is obtained according to an operating method similar tothat of Stage 35.3 of Example 35 using as starting amine,1-[4-(3-bromophenyl)-1H-imidazol-2-yl]-5-methyl-1-hexanamine (obtainedin Stage 7.3; 0.8 g; 0.0019 mol) and as ketone, cyclohexanone (0.32 ml;0.0023 mol). A white-coloured powder is obtained with a yield of 38%.Melting point: 236-238° C.

MH+=418.2.

Example 38N-{1-[4-(4-fluorophenyl)-1H-imidazol-2-yl]heptyl}cyclohexanamine 38.1)tert-butyl 1-[4-(4-fluorophenyl)-1H-imidazol-2-yl]heptylcarbamate

This compound is obtained according to an operating method similar tothat of Stage 31.2 of Example 31 using2-[(tert-butoxycarbonyl)amino]octanoic acid (6.2 g; 0.024 mol) in placeof the N-(butoxycarbonyl)-β-alanine and 2-bromo-4-fluoroacetophenone(5.2 g; 0.024 mol) in place of the 4-phenyl-bromoacetophenone. A whitepowder is obtained (yield: 58%) which is sufficiently pure to be used asit is for the following stage.

38.2) 1-[4-(4-fluorophenyl)-1H-imidazol-2-yl]-1-heptanamine

This compound is obtained according to an operating method similar tothat of Stage 32.2 of Example 32 using as starting compound tert-butyl1-[4-(4-fluorophenyl)-1H-imidazol-2-yl]heptylcarbamate (5.2 g; 0.014mol). After purification on a silica column (eluent:CH₂Cl₂-MeOH—NH₄OH/89-10-1), a grey-coloured powder is obtained (yield of72%). Melting point: 148-150° C.

MH+=276.2.

38.3) N-{1-[4-(4-fluorophenyl)-1H-imidazol-2-yl]heptyl}cyclohexanamine

This compound is obtained according to an operating method similar tothat of Stage 35.3 of Example 35 using as starting amine,1-[4-(4-fluorophenyl)-1H-imidazol-2-yl)-1-heptanamine (0.5 g; 0.0014mol) and as ketone, cyclohexanone (0.17 ml; 0.0014 mol). Awhite-coloured powder is obtained with a yield of 15%.

Melting point: 190-192° C.

MH+=358.2.

Example 39(1R)—N-benzyl-1-(1-benzyl-4-tert-butyl-1H-imidazol-2-yl)-2-(1H-indol-3-yl)ethanamine

Triethylamine (0.83 ml; 0.006 mol) is added at 23° C. to a solutioncontaining(1R)-1-(1-benzyl-4-tert-butyl-1H-imidazol-2-yl)-2-(1H-indol-3-yl)ethanamine(0.7 g; 0.002 mol; prepared under experimental conditions similar tothose previously and using suitable starting reagents and reactionproducts) in 15 ml of acetonitrile. The mixture is stirred for one hourat 23° C. then benzyl chloride (0.23 ml; 0.002 mol) is added. Stirringis maintained for 16 hours. The reaction mixture is concentrated using arotary evaporator and the oil obtained is taken up in ethyl acetate andwater. The aqueous phase is extracted with ethyl acetate and washed withwater then with a saturated solution of sodium chloride. The solventsare evaporated off under vacuum. After purification on a silica column(eluent: AE-heptane/7-3), a deep beige-coloured solid is obtained in theform of a paste (yield of 5% c). Free base. Melting point: 60-62° C.

MH+=463.3.

Example 40(R,S)—N-benzyl-1-(1-benzyl-4-phenyl-1-H-imidazol-2-yl)-1-heptanamine

(R,S)-1-(4-phenyl-1H-imidazol-2-yl)heptylamine (1 g; 0.003 mol; preparedunder experimental conditions similar to those previously and usingsuitable starting reagents and reaction products) is diluted in 20 ml ofdimethylformamide. Potassium carbonate (2.2 g; 0.016 mol) is added at23° C. then benzyl bromide (1.2 ml; 0.010 mol) is added fairly slowly.The mixture is stirred for 72 hours at 23° C. before being poured intoice-cooled water. The mixture is extracted with ethyl acetate. Theorganic phase is washed with water then with a saturated solution ofsodium chloride. After drying over magnesium sulphate, the solvents areconcentrated using a rotary evaporator. After purification on a silicacolumn (eluent: ethyl acetate-heptane/10-90), a white-coloured powder isobtained (yield of 31%). Free base. Melting point: 94-96° C.

MH+=438.3.

Example 41N-benzyl-N-[(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)methyl]-1-hexanamine

N-benzyl(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)methanamine (1 g;0.0024 mol; prepared under experimental conditions similar to thosepreviously and using suitable starting reagents and reaction products)is diluted in 15 ml of dimethylformamide. Potassium carbonate (1 g;0.0073 mol) is added at 23° C. then hexane bromide (0.34 ml; 0.0024 mol)is added fairly slowly. The reaction mixture is brought to about 70° C.for 3 hours before being poured into ice-cooled water. The mixture isextracted with ethyl acetate and the organic phase is washed with water.After drying over magnesium sulphate, the solvents are concentratedusing a rotary evaporator. After purification on a silica column(eluent: ethyl acetate-heptane/7-3), a light yellow-coloured solid isobtained in the form of a paste (yield of 13%). Free base. Meltingpoint: 120-122° C.

MH+=424.3.

Example 42N-benzyl(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)-N-methylmethanamine

(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)-N-methylmethanamine (1 g;0.003 mol; prepared under experimental conditions similar to thosepreviously and using suitable starting reagents and reaction products)is diluted in 20 ml of dimethylformamide. Potassium carbonate (1.23 g;0.009 mol) is added at 23° C. then benzyl bromide (0.34 ml; 0.003 mol)is added fairly slowly. The reaction mixture is stirred at thistemperature for 48 hours then poured in ice-cooled water. The mixture isextracted with ethyl acetate and the organic phase washed with water.After drying over magnesium sulphate, the solvents are concentratedusing a rotary evaporator. After purification on a silica column(eluent: ethyl acetate-heptane/8-2), a white-coloured solid is obtainedin the form of a paste (yield of 16%). Free base. Melting point:106-108° C.

MH+=354.2.

Example 43 (R,S)—N,N-dihexyl-1-(4-phenyl-1H-imidazol-2-yl)-1-heptanamine

(R,S)-1-(4-phenyl-1H-imidazol-2-yl)-1-heptanamine (1 g; 0.003 mol;prepared under experimental conditions similar to those previously andusing suitable starting reagents and reaction products) is diluted in 10ml of methanol. Triethylamine (0.9 ml; 0.006 mol) is added dropwise thenthe mixture is stirred for 30 minutes at 23° C. Hexanal (0.45 ml; 0.0036mol) is then added then the mixture is stirred for one hour at 23° C.Sodium triacetoxyborohydride (1.3 g; 0.006 mol) is finally added. Afterstirring for two hours at 23° C., water is added and the reactionmixture is extracted with ethyl acetate. The organic phase is washedwith water and dried over magnesium sulphate before evaporation of thesolvents. After purification on a silica column (eluent: ethylacetate-heptane/6-4), a brown-coloured solid is obtained in the form ofa paste (yield of 3%). Free base. The melting point could not bemeasured (paste).

MH+=426.4.

Example 44N-[(1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]-2-pyrimidinamine

(1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)ethanamine (2 g;0.0066 mol; prepared under experimental conditions similar to thosepreviously and using suitable starting reagents and reaction products)is diluted in 10 ml of n-butanol. 2-bromopyrimidine (1 g; 0.0066 mol)then diisoethylamine (1.15 ml, 0.0066 mol) are added dropwise. Themixture is then heated to about 80° C. for 16 hours. The n-butanol isevaporated off then the residue is taken up in water and ethyl acetate.The organic phase is washed with water then with a saturated solution ofsodium chloride before being dried over magnesium sulphate andconcentrated using a rotary evaporator. After purification on a silicacolumn (eluent: ethyl acetate-heptane/7-3 thenCH₂Cl₂-MeOH—NH₄OH/95-4.5-0.5 then ethyl acetate), a white-colouredpowder is obtained (the yield is 20%). Free base. Melting point:138-140° C.

MH+=381.2.

Example 45 (1-benzyl-4-phenyl-1H-imidazol-2-yl)-N,N-dimethylmethanamine

(1-benzyl-4-phenyl-1H-imidazol-2-yl)methanamine (0.6 g; 0.0018 mol;prepared under experimental conditions similar to those previously andusing suitable starting reagents and reaction products) is diluted in 15ml of tetrahydrofuran. Triethylamine (1.12 ml; 0.008 mol) then methyl4-toluenesulphonate (0.75 g; 0.004 mol) are added dropwise. The mixtureis stirred for 48 hours at 23° C. then poured into ice-cooled water.After extraction with ether then decantation, the organic phase iswashed with water then with a saturated solution of sodium chloride. Theorganic phase is then dried over magnesium sulphate and concentratedusing a rotary evaporator. After purification on a silica column(eluent: ethyl acetate-heptane/7-3 then CH₂Cl₂-MeOH/95-5), awhite-coloured powder is obtained (yield of 44%). Free base. Meltingpoint: 78-80° C.

MH+=292.2.

Example 46(1R)—N-benzyl-2-(1H-indol-3-yl)-N-methyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine

(1R)—N-benzyl-2-(1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)ethanamine(0.5 g; 0.00127 mol; prepared under experimental conditions similar tothat of Example 38 and using suitable starting reagents and reactionproducts) is diluted in 25 ml of tetrahydrofuran. Methyl tosylate (0.24g; 0.00127 mol) is added to the previous solution at 23° C. thenpotassium tert-butylate (0.15 g; 0.00127 mol) is added fairly slowly.Stirring is maintained for two hours at 23° C. then the mixture isheated to about 60° C. for eight hours. The solvent is evaporated offand the residue obtained taken up in ethyl acetate and a 10% solution ofsodium bicarbonate. After decantation, the organic phase is washed withwater and dried over magnesium sulphate. The solvent is then evaporatedoff. After purification on a silica column (eluent: ethylacetate-heptane/7-3), a light beige-coloured solid is obtained in theform of a paste (yield of 4%). Free base. Melting point: 110-112° C.

MH+=407.3.

The compounds of Examples 47 to 318 are obtained, according toprocedures similar to those described for Examples 31 to 46 or above iiithe part entitled “Preparation of the compounds of general formula (I)”.

Example 47(1R)-2-(1H-indol-3-yl)-N-(2-phenylethyl)-1-(4-phenyl-1H-imidazol-2-yl)ethanamine

Free base. The melting point could not be measured (paste).

Example 48(1R)—N-benzyl-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine

Free base. Melting point: 228-230° C.

Example 49 N-benzyl(4-phenyl-1H-imidazol-2-yl)methanamine

Free base. The melting point could not be measured (paste).

Example 50tert-butyl(1R)-1-(4-tert-butyl-1H-imidazol-2-yl)-2-(1H-indol-3-yl)-ethylcarbamate

Free base. Melting point: 104-106° C.

Example 51: (4-phenyl-1H-imidazol-2-yl)methanamine

Hydrochloride. Melting point: 228-230° C.

Example 52 1-methyl-1-(4-phenyl-1H-imidazol-2-yl)ethylamine

Hydrochloride. Melting point: 200-204° C.

Example 53N-[(1S)-2-(1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]-1-hexanamine

Hydrochloride. Melting point: 132-134° C.

Example 54 tert-butyl(R,S)-1-(4-phenyl-1H-imidazol-2-yl)heptylcarbamate

Free base. Melting point: 102-104° C.

Example 55 (4-[1,1′-biphenyl]-4-yl-1-methyl-1H-imidazol-2-yl)methanamine

Hydrochloride. Melting point: 279-280° C.

Example 56 (1S)-3-methyl-1-(4-phenyl-1H-imidazol-2-yl)-1-butanamine

Hydrochloride. Melting point: 150-152° C.

Example 57 butyl 2-[4-(4-phenoxyphenyl)-1H-imidazol-2-yl]ethylcarbamate

Free base. The melting point could not be measured (paste).

Example 58(R,S)—N-[2-(1-methyl-1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]-1-butanamine

Free base. The melting point could not be measured (paste).

Example 59(R,S)-4-(2-{1-[(tert-butoxycarbonyl)amino]pentyl}-1H-imidazol-4-yl)-1,1′-biphenyl

Free base. Melting point: 172-176° C.

Example 60(R,S)—N-benzyl-1-(4-[1,1′-biphenyl]-4-yl-1-H-imidazol-2-yl)-1-pentanamine

Free base. Melting point: 201-203° C.

Example 61N-[2-(4-[1,1′-biphenyl]-4-yl-]1H-imidazol-2-yl)ethyl]-3,3-dimethyl-butanamide

Free base. Melting point: 186-188° C.

Example 62(1R)—N-benzyl-1-(4,5-dimethyl-1,3-oxazol-2-yl)-2-(1H-indol-3-yl)ethanamine

Free base. The melting point could not be measured (paste).

Example 63 tert-butyl(R,S)-1-(4-phenyl-1H-imidazol-2-yl)hexylcarbamate

Free base. The melting point could not be measured (paste).

Example 64 (R,S)—N-hexyl-1-(4-phenyl-1H-imidazol-2-yl)-1-heptanamine

Free base. Melting point: 140-142° C.

Example 65 (R,S)-1-(4-phenyl-1H-imidazol-2-yl)hexylamine

Hydrochloride. Melting point: 146-148° C.

Example 66(R,S)—N-benzyl-1-[4-(4-methoxyphenyl)-1H-imidazol-2-yl]-1-heptanamine

Hydrochloride. Melting point: from 115° C.

Example 67(R,S)—N-(2,6-dichlorobenzyl)-1-(4-phenyl-1H-imidazol-2-yl)-1-heptanamine

Free base. The melting point could not be measured (paste).

Example 68(R,S)—N-(4-chlorobenzyl)-1-(4-phenyl-1H-imidazol-2-yl)-1-heptanamine

Free base. The melting point could not be measured (paste).

Example 69 (R,S)-1-[4-(3-methoxyphenyl)-1-H-imidazol-2-yl]heptylamine

Hydrochloride. Melting point: 110-112° C.

Example 70(R,S)—N-(2-chlorobenzyl)-1-(4-phenyl-1H-imidazol-2-yl)-1-heptanamine

Free base. The melting point could not be measured (paste).

Example 71(R,S)—N-(2-fluorobenzyl)-1-(4-phenyl-1H-imidazol-2-yl)-1-heptanamine

Free base. The melting point could not be measured (paste).

Example 72 (R,S)—N-butyl-1-(4-phenyl-1-H-imidazol-2-yl)-1-heptanamine

Free base. The melting point could not be measured (paste).

Example 73(R,S)—N-isopentyl-N-[1-(4-phenyl-1H-imidazol-2-yl)heptyl]amine

Free base. The melting point could not be measured (paste).

Example 74(R,S)-1-[4-(3-bromophenyl)-1H-imidazol-2-yl]-N-hexyl-1-heptanamine

Free base. The melting point could not be measured (paste).

Example 75 (R,S)—N-pentyl-1-(4-phenyl-1H-imidazol-2-yl)-1-heptanamine

Free base. Melting point: 118-120° C.

Example 76 (R,S)—N-[1-(4-phenyl-1-H-imidazol-2-yl)heptyl]cyclohexanamine

Free base. Melting point: 68-70° C.

Example 77(R,S)—N-benzyl-1-[4-(3,4-dichlorophenyl)-1-H-imidazol-2-yl]-1-heptanamine

Free base. Melting point: 192-194° C.

Example 78 butyl(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)methylcarbamate

Free base. Melting point: 130-132° C.

Example 79 (R,S)—N-[1-(4-phenyl-1H-imidazol-2-yl)heptyl]cyclopentanamine

Free base. The melting point could not be measured (paste).

Example 80 (S)-cyclohexyl(4-phenyl-1H-imidazol-2-yl)methylamine

Hydrochloride. Melting point: 208-210° C.

Example 81(R,S)—N-{1-[4-(2-chlorophenyl)-1H-imidazol-2-yl]heptyl}-cyclohexanamine

Hydrochloride. Melting point: 155-157° C.

Example 82N—[(S)-cyclohexyl(4-cyclohexyl-1H-imidazol-2-yl)methyl]-cyclohexanamine

Hydrochloride. Melting point: 180-182° C.

Example 83N—[(S)-cyclohexyl(4-phenyl-1H-imidazol-2-yl)methyl]-cyclobutanamine

Hydrochloride. Melting point: 210-212° C.

Example 84(R,S)—N-{1-[4-(4-fluorophenyl)-1-H-imidazol-2-yl]heptyl}-cyclobutanamine

Hydrochloride. Melting point: 144-146° C.

Example 85N-{(S)-cyclohexyl[4-(3-fluoro-4-methoxyphenyl)-1H-imidazol-2-yl]methyl}cyclobutanamine

Free base. Melting point: from 95° C.

Example 86N—((S)-cyclohexyl{4-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}methyl)cyclobutanamine

Free base. Foam.

Example 87N-{((S)-cyclohexyl[4-(3-fluorophenyl)-1H-imidazol-2-yl]methyl}-cyclobutanamine

Free base. Melting point: 172-176° C.

Example 88(1R)—N-benzyl-2-(1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)ethanamine

Free base. Melting point: 100-102° C.

Example 89(R,S)-2-(1H-indol-3-yl)-1-(5-methyl-4-phenyl-1H-imidazol-2-yl)ethanamine

Hydrochloride. Melting point: 208-210° C.

Example 90(1R)-1-(4,5-diphenyl-1H-imidazol-2-yl)-2-(1H-imidol-3-yl)ethanamine

Hydrochloride. Melting point: >260° C.

Example 91 (R,S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine

Hydrochloride. Melting point: 180-182° C.

Example 92(R,S)-2-(1-methyl-1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)ethylamine

Hydrochloride. Melting point: 110-114° C.

Example 93(1S)—N-benzyl-2-(1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)ethanamine

Free base. Melting point: 118-120° C.

Example 94(1R)—N-benzyl-1-(4,5-diphenyl-1-H-imidazol-2-yl)-2-(1H-indol-3-yl)ethanamine

Free base. Melting point: 146-148° C.

Example 95(1R)—N-benzyl-2-(1H-indol-3-yl)-1-(5-methyl-4-phenyl-1H-imidazol-2-yl)ethanamine

Free base. Melting point: 120-122° C.

Example 96tert-butyl(1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)-ethylcarbamate

Free base. Melting point: 208-210° C.

Example 97(1R)-2-(1-H-indol-3-yl)-1-(4-phenyl-1-H-imidazol-2-yl)ethanamine

Hydrochloride. The melting point could not be measured (paste).

Example 98N-[(1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]benzamide

Free base. Melting point: 218-220° C.

Example 99benzyl(1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)ethylcarbamate

Free base. Melting point: 105-108° C.

Example 100(1R)—N-benzyl-2-(1H-indol-3-yl)-1-(4-phenyl-1,3-thiazol-2-yl)ethanamine

Free base. Melting point: 134-136° C.

Example 101N-[(1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1,3-thiazol-2-yl)-ethyl]benzamide

Free base. Melting point: 108-110° C.

Example 102tert-butyl(1R)-2-(1H-indol-3-yl)-1-[4-(4-nitrophenyl)-1H-imidazol-2-yl]-ethylcarbamate

Free base. Melting point: 220-222° C.

Example 103 tert-butyl(4-phenyl-1H-imidazol-2-yl)methylcarbamate

Free base. Melting point: 170-172° C.

Example 104tert-butyl(1-benzyl-4-phenyl-1H-imidazol-2-yl)methylcarbamate

Free base. Melting point: 140-142° C.

Example 105(R,S)—N-benzyl-2-(6-fluoro-1-H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)ethanamine

Free base. Melting point: 98-100° C.

Example 106(1R)-2-(1H-indol-3-yl)-1-[4-(4-nitrophenyl)-1H-imidazol-2-yl]ethanamine

Hydrochloride. Melting point: becomes pasty at about 220° C.

Example 107 (1-benzyl-4-phenyl-1H-imidazol-2-yl)methanamine

Hydrochloride. Melting point: 248-250° C.

Example 108(1R)-2-(1H-indol-3-yl)-N-(2-phenoxyethyl)-1-(4-phenyl-1H-imidazol-2-yl)ethanamine

Free base. Melting point: 94-96° C.

Example 109(1R)-1-(4-tert-butyl-1H-imidazol-2-yl)-2-(1H-indol-3-yl)ethylamine

Hydrochloride. Melting point: 230-232° C.

Example 110 N-benzyl(1-benzyl-4-phenyl-1H-imidazol-2-yl)methanamine

Free base. Melting point: 60-62° C.

Example 111(1R)-2-(1-benzothien-3-yl)-N-benzyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine

Free base. Melting point: 152-154° C.

Example 112(1R)-2-(1H-indol-3-yl)-N-(2-phenoxyethyl)-1-(4-phenyl-1,3-thiazol-2-yl)ethanamine

Free base. Melting point: 124-126° C.

Example 113 tert-butyl 1-(4-phenyl-1H-imidazol-2-yl)cyclohexylcarbamate

Free base. Melting point: 170-172° C.

Example 114tert-butyl(R,S)-2-(6-chloro-1-H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)ethylcarbamate

Free base. Melting point: 208-210° C.

Example 115 1-(4-phenyl-1H-imidazol-2-yl)cyclohexanamine

Hydrochloride. Melting point: 202-204° C.

Example 116N-[(1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]-N′-phenylurea

Free base. Compound described in the PCT Application WO 99/64401.

Example 117N-[(1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]benzenecarboximidamide

Free base. Compound described in the PCT Application WO 99/64401.

Example 118(1R)—N-(cyclohexylmethyl)-2-(1H-indol-3-yl)-1-(4-phenyl-1-H-imidazol-2-yl)ethanamine

Free base. Compound described in the PCT Application WO 99/64401.

Example 119(R,S)—N¹-benzyl-1-(4-phenyl-1H-imidazol-2-yl)-1,5-pentanediamine

Free base. Compound described in the PCT Application WO 99/64401.

Example 120tert-butyl(R,S)-5-(benzylamino)-5-(4-phenyl-1-H-imidazol-2-yl)pentylcarbamate

Free base. Compound described in the PCT Application WO 99/64401.

Example 121N-[(1R)-2-(1-H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]-4-methoxybenzenecarboximidamide

Free base. Compound described in the PCT Application WO 99/64401.

Example 122(R,S)-2-(6-chloro-1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)ethylamine

Hydrochloride. Melting point: 210-212° C.

Example 123 N-benzyl-1-(4-phenyl-1H-imidazol-2-yl)cyclohexanamine

Free base. Melting point: 114-116° C.

Example 124tert-butyl(1R)-3-methyl-1-(4-phenyl-1H-imidazol-2-yl)butylcarbamate

Free base. Melting point: 88-90° C.

Example 125(1R)—N-benzyl-3-methyl-1-(4-phenyl-1H-imidazol-2-yl)-1-butanamine

Free base. Melting point: 134-135° C.

Example 126tert-butyl(R,S)-phenyl(4-phenyl-1H-imidazol-2-yl)methylcarbamate

Free base. Melting point: 134-136° C.

Example 127 tert-butyl1-methyl-1-(4-phenyl-1H-imidazol-2-yl)ethylcarbamate

Free base. Melting point: 130-132° C.

Example 128 (R,S)-phenyl(4-phenyl-1H-imidazol-2-yl)methylamine

Hydrochloride. The melting point could not be measured (paste).

Example 129tert-butyl(1R)-3-phenyl-1-(4-phenyl-1H-imidazol-2-yl)propylcarbamate

Free base. Melting point: 72-74° C.

Example 130tert-butyl(1R)-2-cyclohexyl-1-(4-phenyl-UH-imidazol-2-yl)ethylcarbamate

Free base. Melting point: 184-185° C.

Example 131 (1R)-3-phenyl-1-(4-phenyl-1H-imidazol-2-yl)-1-propanamine

Hydrochloride. Melting point: 174-176° C.

Example 132 (1R)-2-cyclohexyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine

Hydrochloride. Melting point: 196-198° C.

Example 133 (R,S)—N-benzyl(phenyl)(4-phenyl-1H-imidazol-2-yl)methanamine

Free base. Melting point: 144-146° C.

Example 134(1R)—N-benzyl-2-cyclohexyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine

Free base. Melting point: 52-54° C.

Example 135(1R)—N-benzyl-3-phenyl-1-(4-phenyl-1H-imidazol-2-yl)-1-propanamine

Free base. Melting point: 142-144° C.

Example 136(R,S)—N-{5,5,5-trifluoro-1-[4-(4-fluorophenyl)-1H-imidazol-2-yl]pentyl}cyclohexanamine

Free base. Melting point: 220° C.

Example 1374-(2-{[(tert-butoxycarbonyl)amino]methyl}-1H-imidazol-4-yl)-1,1′-biphenyl

Free base. Melting point: 100-102° C.

Example 138N-{(S)-cyclohexyl[4-(4-methylsulphonylphenyl)-1H-imidazol-2-yl]methyl}cyclohexanamine

Free base. Melting point: 152-154° C.

Example 139 N-benzyl-2-(4-phenyl-1H-imidazol-2-yl)-2-propanamine

Free base. Melting point: 136-138° C.

Example 1404-(1-benzyl-2-{[[(tert-butoxycarbonyl)amino]methyl}-1H-imidazol-4-yl)-1,1′-biphenyl

Free base. Melting point: 167-169° C.

Example 141 (4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)methanamine

Hydrochloride. Melting point: 240-242° C.

Example 142 (R,S) 1-(4-phenyl-1H-imidazol-2-yl)heptylamine

Hydrochloride. Melting point: 131-134° C.

Example 143 (1-benzyl-4-[1,1′-biphenyl]-4-yl-H-imidazol-2-yl)methanamine

Hydrochloride. Melting point: 170-174° C.

Example 144N,N-dibenzyl(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)methanamine

Free base. Melting point: 70-74° C.

Example 145 (R,S)—N-benzyl-1-(4-phenyl-1-H-imidazol-2-yl)-1-heptanamine

Free base. Melting point: 160-162° C.

Example 1464-(2-{[(tert-butoxycarbonyl)amino]methyl}-1-methyl-1H-imidazol-4-yl)-1,1′-biphenyl

Free base. Melting point: 208-210° C.

Example 147tert-butyl(1S)-1-(4,5-diphenyl-1-H-imidazol-2-yl)-2-(1H-indol-3-yl)ethylcarbamate

Free base. Melting point: 142-143° C.

Example 148tert-butyl(1R)-2-(1H-indol-3-yl)-1-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethylcarbamate

Free base. Melting point: 96-100° C.

Example 1494-(2-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-1H-imidazol-4-yl)-1,1′-biphenyl

Free base. Melting point: 72-74° C.

Example 1504-(2-{(1R)-1-[(tert-butoxycarbonyl)amino]-2-cyclohexylethyl}-1H-imidazol-4-yl)-1,1′-biphenyl

Free base. Melting point: 112-114° C.

Example 151(1R)-2-(1H-indol-3-yl)-1-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethanamine

Hydrochloride. Melting point: 206-210° C.

Example 1524-(2-{2-[(tert-butoxycarbonyl)amino]ethyl}-1H-imidazol-4-yl)-1,1′-biphenyl

Free base. Melting point: 140-142° C.

Example 153 tert-butylmethyl[(5-methyl-4-phenyl-1H-imidazol-2-yl)methyl]carbamate

Free base. Melting point: 70-72° C.

Example 154(1R)-1-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)-2-cyclohexylethanamine

Hydrochloride. Melting point: 178-180° C.

Example 155(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)-N-methylmethanamine

Hydrochloride. Melting point: 218-220° C.

Example 156tert-butyl(4,5-diphenyl-1H-imidazol-2-yl)methyl(methyl)carbamate

Free base. Melting point: 170-172° C.

Example 157 tert-butyl(4,5-diphenyl-1H-imidazol-2-yl)methylcarbamate

Free base. Melting point: 144-146-C.

Example 158 N-methyl-(5-methyl-4-phenyl-]1H-imidazol-2-yl)methanamine

Hydrochloride. Melting point: 218-220° C.

Example 159(R,S)—N,N-dibenzyl-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-1-heptanamine

Hydrochloride. Melting point: 130-132° C.

Example 160 (4,5-diphenyl-1H-imidazol-2-yl)methanamine

Hydrochloride. Melting point: 210-212° C.

Example 161 2-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)ethanamine

Hydrochloride. Melting point: 228-230° C.

Example 162 (4,5-diphenyl-1H-imidazol-2-yl)-N-methylmethanamine

Hydrochloride. Melting point: 198-200° C.

Example 163 N-benzyl(4,5-diphenyl-1H-imidazol-2-yl)methanamine

Free base. Melting point: 160-162° C.

Example 164N-benzyl-2-(4-[1,1′-biphenyl]-4-yl-1-imidazol-2-yl)ethanamine

Free base. Melting point: 174-176° C.

Example 1654-(2-{[benzyl(tert-butoxycarbonyl)amino]methyl}-1H-imidazol-4-yl)-1,1′-biphenyl

Free base. Melting point: 130-132° C.

Example 166(1R)-1-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)-3-phenyl-1-propanamine

Hydrochloride. Melting point: 215-218° C.

Example 1674-(2-{(1R)-1-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}-1H-imidazol-4-yl)-1,1′-biphenyl

Free base. Melting point: 154-156° C.

Example 168 N-benzyl(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)methanamine

Hydrochloride. Melting point: >250° C.

Example 169(1R)—N-benzyl-1-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)-2-cyclohexylethanamine

Free base. Melting point: 233-238° C.

Example 170(1R)—N-benzyl-1-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)-3-phenyl-1-propanamine

Free base. Melting point: 210-213° C.

Example 1714-(2-{3-[(tert-butoxycarbonyl)amino]propyl}-1H-imidazol-4-yl)-1,1′-biphenyl

Free base. Melting point: 145-146° C.

Example 1724-[2-(2-{[(tert-butylamino)carbothioyl]amino}ethyl)-1H-imidazol-4-yl]-1,1′-biphenyl

Free base. Melting point: 98-99° C.

Example 173 tert-butyl 6-(4-phenyl-1H-imidazol-2-yl)hexylcarbamate

Free base. The melting point could not be measured (paste).

Example 174 tert-butyl(R,S)-1-(4-phenyl-1H-imidazol-2-yl)pentylcarbamate

Free base. Melting point: 126° C.

Example 175(R,S)-1-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)-1-pentanamine

Hydrochloride. Melting point: 197-200° C.

Example 176N-[2-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)ethyl]-1-hexanamine

Free base. Melting point: 152-154° C.

Example 1774-[2-(2-{[(tert-butylamino)carbonyl]amino}ethyl)-1H-imidazol-4-yl]-1,1′-biphenyl

Free base. Melting point: 195-196° C.

Example 178N-benzyl-3-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)-1-propanamine

Free base. Melting point: 254-256° C.

Example 179 3-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)-1-propanamine

Hydrochloride. Melting point: >260° C.

Example 180 6-(4-phenyl-1H-imidazol-2-yl)hexylamine

Hydrochloride. Melting point: 244-246° C.

Example 181 (R,S)-1-(4-phenyl-1H-imidazol-2-yl)pentylamine

Hydrochloride. Melting point: 178-180° C.

Example 182tert-butyl(R,S)-1-[4-(4-methylphenyl)-1H-imidazol-2-yl]heptylcarbamate

Free base. Melting point: 77-80° C.

Example 183tert-butyl(R,S)-1-[4-(2-methoxyphenyl)-1H-imidazol-2-yl]heptylcarbamate

Free base. Melting point: 64-65° C.

Example 184 (R,S)-1-[4-(4-methylphenyl)-1H-imidazol-2-yl]-1-heptanamine

Hydrochloride. Melting point: 157-160° C.

Example 185 (R,S)-1-[4-(2-methoxyphenyl)-1H-imidazol-2-yl]heptylamine

Hydrochloride. Melting point: 238-240° C.

Example 186 (R,S)—N-benzyl-1-(4-phenyl-1H-imidazol-2-yl)-1-pentanamine

Free base. Melting point: 200-202° C.

Example 187tert-butyl(R,S)-1-[4-(4-methoxyphenyl)-1R-imidazol-2-yl]heptylcarbamate

Free base. Melting point: 125-127° C.

Example 188(R,S)-1-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)-1-heptanamine

Hydrochloride. Melting point: 182-184° C.

Example 189tert-butyl(R,S)-1-[4-(3-bromophenyl)-1H-imidazol-2-yl]heptylcarbamate

Free base. Melting point: 141-143° C.

Example 190 (R,S)-1-[4-(4-methoxyphenyl)-1H-imidazol-2-yl]heptylamine

Hydrochloride. Melting point: 231-232° C.

Example 191 (R,S)-1-[4-(3-bromophenyl)-1H-imidazol-2-yl]-1-heptanamine

Hydrochloride. Melting point: 230-231° C.

Example 192(R,S)-4-(2-{1-[(tert-butoxycarbonyl)amino]heptyl}-1H-imidazol-4-yl)-1,1′-biphenyl

Free base. Melting point: 142-144° C.

Example 193(R,S)—N-benzyl-1-[4-(3-bromophenyl)-1H-imidazol-2-yl-1-heptanamine

Acetate. Melting point: 115-116° C.

Example 1944-(2-{(1S)-1-[(tert-butoxycarbonyl)amino]propyl}-1H-imidazol-4-yl)-1,1′-biphenyl

Free base. Melting point: 138-140° C.

Example 195(R,S)—N-benzyl-1-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)-1-heptanamine

Free base. Melting point: 100-102° C.

Example 196(1S)-1-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)-1-propanamine

Hydrochloride. Melting point: >250° C.

Example 197tert-butyl(1S)-1-(4,5-diphenyl-1H-imidazol-2-yl)propylcarbamate

Free base. Melting point: 136-138° C.

Example 198(1S)—N-benzyl-1-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)-1-propanamine

Free base. Melting point: 220-222° C.

Example 199 (1S)-1-(4,5-diphenyl-1H-imidazol-2-yl)-1-propanamine

Hydrochloride. Melting point: 224-226° C.

Example 200(R,S)—N-benzyl-1-[4-(4-methylphenyl)-1H-imidazol-2-yl]-1-heptanamine

Hydrochloride. Melting point: 185-188° C.

Example 201(R,S)—N-benzyl-1-[4-(2-methoxyphenyl)-1H-imidazol-2-yl]-1-heptanamine

Free base. Melting point: 155-157° C.

Example 202 (R,S)—N-benzyl-1-(4-phenyl-1H-imidazol-2-yl)-1-hexanamine

Free base. Melting point: 192-194° C.

Example 2034-[2-(2-{[(neopentyloxy)carbonyl]amino}ethyl)-1H-imidazol-4-yl]-1,1′-biphenyl

Free base. Melting point: 162-164° C.

Example 204(1S)—N-benzyl-1-(4,5-diphenyl-1H-imidazol-2-yl)-1-propanamine

Free base. Melting point: 182-184° C.

Example 205 (R,S)-4-[2-(1-aminoheptyl)-1H-imidazol-4-yl]benzonitrile

Hydrochloride. Melting point: 218-220° C.

Example 206 (R,S)-1-[4-(4-bromophenyl)-1H-imidazol-2-yl]-1-heptanamine

Free base. Melting point: from 126° C.

Example 207 tert-butyl(1R)-1-(4-phenyl-1-H-imidazol-2-yl)butylcarbamate

Free base. Melting point: 156-158° C.

Example 2084-(2-{(1R)-1-[(tert-butoxycarbonyl)amino]butyl}-1H-imidazol-4-yl)-1,1′-biphenyl

Free base. Melting point: 145.6° C.

Example 209(1R)-1-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)-1-butanamine

Hydrochloride. Melting point: 155.4° C.

Example 210(R,S)-4-[2-(1-aminoheptyl)-1H-imidazol-4-yl]-2,6-di(tert-butyl)-phenol

Hydrochloride. Melting point: 204-206° C.

Example 211 (1R)-1-(4-phenyl-1H-imidazol-2-yl)-1-butanamine

Hydrochloride. Melting point: 182-184° C.

Example 212(R,S)—N-benzyl-1-[4-(4-bromophenyl)-1H-imidazol-2-yl]-1-heptanamine

Free base. Melting point: becomes pasty from 130° C.

Example 213(1R)—N-benzyl-1-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)-1-butanamine

Free base. Melting point: 78.6° C.

Example 214 (1R)—N-benzyl-1-(4-phenyl-1H-imidazol-2-yl)-1-butanamine

Free base. Melting point: 218-220° C.

Example 215(R,S)—N-(3-chlorobenzyl)-1-(4-phenyl-1H-imidazol-2-yl)-1-heptanamine

Free base. The melting point could not be measured (paste).

Example 216(R,S)—N-benzyl-1-[4-(3-methoxyphenyl)-1H-imidazol-2-yl]-1-heptanamine

Free base. Melting point: 141-142° C.

Example 217(R,S)-4-{2-[1-(benzylamino)heptyl]-1H-imidazol-4-yl}benzonitrile Freebase. Melting point: 188-189° C. Example 218(R,S)-4-[2-(1-aminoheptyl)-1-H-imidazol-4-yl]-N,N-diethylaniline

Hydrochloride. Melting point: 192° C.

Example 219 (1R)-1-(4-phenyl-1H-imidazol-2-yl)ethanamine

Hydrochloride. Melting point: 178-181° C.

Example 220 (R,S)-1-[4-(4-fluorophenyl)-1H-imidazol-2-yl]-1-heptanamine

Hydrochloride. Melting point: 148-150° C.

Example 221 (R,S)-1-[4-(2-chlorophenyl)-1H-imidazol-2-yl]-1-heptanamine

Hydrochloride. Melting point: 138-140° C.

Example 222N-[(1S)-1-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)propyl]-1-butanamine

Free base. The melting point could not be measured (paste).

Example 223 (1R)—N-benzyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine

Free base. The melting point could not be measured (paste).

Example 224 (R,S)—N-[1-(4-phenyl-1H-imidazol-2-yl)heptyl]-N-propylamine

Free base. Melting point: 94-98° C.

Example 225(R,S)—N-benzyl-1-[4-(3-methoxyphenyl)-1H-imidazol-2-yl]-1-heptanamine

Hydrochloride. Melting point: from 120° C.

Example 226(R,S)-4-{2-[1-(benzylamino)heptyl]-1-H-imidazol-4-yl}benzonitrile

Hydrochloride. Melting point: from 185° C.

Example 227(R,S)—N-(4-methoxybenzyl)-1-(4-phenyl-1H-imidazol-2-yl)-1-heptanamine

Free base. Melting point: 126-128° C.

Example 228(R,S)—N-benzyl-1-[4-(4-fluorophenyl)-1H-imidazol-2-yl]-1-heptanamine

Hydrochloride. Melting point: from 110° C.

Example 229(R,S)—N-benzyl-1-[4-(2-chlorophenyl)-1H-imidazol-2-yl]-1-heptanamine

Hydrochloride. Melting point: from 90° C.

Example 230(R,S)—N-benzyl-N-(1-{4-[4-(diethylamino)phenyl]-1H-imidazol-2-yl}heptyl)amine

Hydrochloride. Melting point: 170° C.

Example 231(R,S)-1-[4-(3,4-dichlorophenyl)-1H-imidazol-2-yl]-1-heptanamine

Hydrochloride. Melting point: 148-150° C.

Example 232tert-butyl(R,S)-1-[4-(3-bromophenyl)-1-H-imidazol-2-yl]-5-methylhexylcarbamate

Free base. Melting point: 134-136° C.

Example 233(R,S)-1-[4-(3-bromophenyl)-1H-imidazol-2-yl]-5-methyl-1-hexanamine

Hydrochloride. Melting point: 200-202° C.

Example 234(R,S)—N-isobutyl-1-(4-phenyl-]1H-imidazol-2-yl)-1-heptanamine

Acetate. Melting point: 70-72° C.

Example 235(R,S)—N-benzyl-1-[4-(3-bromophenyl)-1H-imidazol-2-yl]-5-methyl-1-hexanamine

Free base. Melting point: 92-94° C.

Example 236(R,S)—N-benzyl-1-[4-(4-methoxyphenyl)-1H-imidazol-2-yl]-1-heptanamine

Free base. Oil.

Example 2374-[2-(2-{[(benzyloxy)carbonyl]amino}ethyl)-1-H-imidazol-4-yl]-1,1′-biphenyl

Free base. Melting point: 134-136° C.

Example 2384-(2-{1-[(butoxycarbonyl)amino]-1-methylethyl}-1H-imidazol-4-yl)-1,1′-biphenyl

Free base. Melting point: 170-172° C.

Example 2394-(2-{2-[(isobutoxycarbonyl)amino]ethyl}-1H-imidazol-4-yl)-1,1′-biphenyl

Free base. Melting point: 134-135° C.

Example 240 (R,S)—N-[1-(4-phenyl-1H-imidazol-2-yl)heptyl]cyclobutanamine

Free base. Melting point: 148-150° C.

Example 2414-(2-{(1S)-1-[(butoxycarbonyl)amino]ethyl}-1-H-imidazol-4-yl)-1,1′-biphenyl

Free base. Melting point: 118-122° C.

Example 2424-(2-{(1R)-1-[(butoxycarbonyl)amino]ethyl}-1H-imidazol-4-yl)-1,1′-biphenyl

Free base. Melting point: 114-116° C.

Example 243N—[(S)-cyclohexyl(4-phenyl-1H-imidazol-2-yl)methyl]-cyclohexanamine

Free base. Melting point: 240-242° C.

Example 2444-(2-{2-[(methoxycarbonyl)amino]ethyl}-1H-imidazol-4-yl)-1,1′-biphenyl

Free base. Melting point: 177.2° C.

Example 2454-(2-{2-[(propoxycarbonyl)amino]ethyl}-1H-imidazol-4-yl)-1,1′-biphenyl

Free base. Melting point: 141.2° C.

Example 2464-(2-{2-[(ethoxycarbonyl)amino]ethyl}-1H-imidazol-4-yl)-1,1′-biphenyl

Free base. Melting point: 132.5° C.

Example 2474-[2-(1-{[(benzyloxy)carbonyl]amino}-1-methylethyl)-1H-imidazol-4-yl]-1,1′-biphenyl

Free base. Melting point: 148-152° C.

Example 248(R,S)—N-isopropyl-N-[1-(4-phenyl-1-H-imidazol-2-yl)heptyl]amine

Free base. Melting point: 114-116° C.

Example 249N-[2-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)ethyl]-cyclohexanamine

Free base. Melting point: 207-210° C.

Example 250(R,S)—N-{1-[4-(3,4-dichlorophenyl)-1H-imidazol-2-yl]heptyl)-cyclohexanamine

Hydrochloride. Melting point: 194° C.

Example 251 butyl 2-[4-(4-fluorophenyl)-1H-imidazol-2-yl]ethylcarbamate

Free base. Melting point: 87° C.

Example 252(R,S)—N-[1-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)heptyl]-cyclohexanamine

Hydrochloride. Melting point: 168-170° C.

Example 253(R,S)-2-(5-fluoro-1-H-indol-3-yl)-1-[4-(4-fluorophenyl)-1H-imidazol-2-yl]ethylamine

Hydrochloride. Melting point: 220-222° C.

Example 254N-([4-(3-bromophenyl)-1H-imidazol-2-yl]methyl}cyclohexanamine

Free base. Melting point: 202-204° C.

Example 255 hexyl2-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)ethylcarbamate

Free base. Melting point: 116.5-116.8° C.

Example 256(R,S)—N-{2-(5-fluoro-1H-indol-3-yl)-1-[4-(4-fluorophenyl)-1H-imidazol-2-yl]ethyl}cyclobutanamine

Hydrochloride. Melting point: 180-190° C.

Example 257(R,S)—N-{1-[4-(4-fluorophenyl)-1-H-imidazol-2-yl]-4-methylpentyl}-cyclohexanamine

Hydrochloride. Melting point: 230-232° C.

Example 258(S)-cyclohexyl[4-(3,4-difluorophenyl)-1H-imidazol-2-yl]-methanamine

Hydrochloride. Melting point: 222-223° C.

Example 259(S)-cyclohexyl[4-(3-fluoro-4-methoxyphenyl)-1H-imidazol-2-yl]-methanamine

Hydrochloride. Melting point: 225-227° C.

Example 260(R,S)-cyclopropyl[4-(4-fluorophenyl)-1H-imidazol-2-yl]-methanamine

Hydrochloride. Melting point: 230-232° C.

Example 261N-{(S)-cyclohexyl[4-(4-fluorophenyl)-1H-imidazol-2-yl]methyl}-2-propanamine

Free base. Melting point: 210-212° C.

Example 262N-{(S)-cyclohexyl[4-(3,4-difluorophenyl)-1H-imidazol-2-yl]methyl}cyclobutanamine

Free base. Melting point: 200-202° C.

Example 263(R,S)N-(cyclohexylmethyl)-1-(4-phenyl-1H-imidazol-2-yl)-1-heptanamine

Hydrochloride. Melting point: 142-144° C.

Example 264N-{(S)-cyclohexyl[4-(4-fluorophenyl)-1H-imidazol-2-yl]methyl}cyclohexanamine

Hydrochloride. Melting point: >250° C.

Example 265(S)-cyclohexyl-N-(cyclohexylmethyl)(4-phenyl-1H-imidazol-2-yl)methanamine

Hydrochloride. Melting point: 180-182° C.

Example 266(R,S)—N-{cyclopropyl[4-(4-fluorophenyl)-1H-imidazol-2-yl]methyl}cyclohexanamine

Hydrochloride. The melting point could not be measured (paste).

Example 267(S)-cyclohexyl-N-(cyclopropylmethyl)(4-phenyl-1H-imidazol-2-yl)methanamine

Hydrochloride. Melting point: 151-152° C.

Example 268 butyl2-[4-(4-cyclohexylphenyl)-1H-imidazol-2-yl]ethylcarbamate

Free base. Melting point: 138.4° C.

Example 2694-[2-(2-{[(cyclohexyloxy)carbonyl]amino}ethyl)-1H-imidazol-4-yl]-1,1′-biphenyl

Free base. Melting point: 150° C.

Example 270N—((S)-cyclohexyl{4-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methyl)-cyclobutanamine

Free base. Melting point: 136-140° C.

Example 2714-[2-(2-{[(cyclopentyloxy)carbonyl]amino}ethyl)-1-H-imidazol-4-yl]-1,1′-biphenyl

Free base. Melting point: 140.5° C.

Example 272(R,S)—N-{1-[4-(3-bromophenyl)-1]-imidazol-2-yl}-5-methylhexyl}-cyclohexanamine

Hydrochloride. Melting point: 216.7° C.

Example 273(S)-cyclohexyl-N-(cyclopropylmethyl)[4-(4-fluorophenyl)-1H-imidazol-2-yl]-methanamine

Hydrochloride. Melting point: 221.4° C.

Example 274(R,S)—N-{cyclopentyl[4-(4-fluorophenyl)-1H-imidazol-2-yl]methyl}cyclobutanamine

Free base. Melting point: 146-148° C.

Example 275N-{(S)-cyclohexyl[4-(4-cyclohexylphenyl)-1H-imidazol-2-yl]methyl}cyclobutanamine

Hydrochloride. Melting point: 190-192° C.

Example 276N-{(1R)-1-[4-(4-fluorophenyl)-1-H-imidazol-2-yl]-2-methylpropyl}-cyclohexanamine

Free base. Melting point: 224-226° C.

Example 277N—((S)-cyclohexyl{4-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-ylmethyl)cyclobutanamine

Acetate. Melting point: from 130° C.

Example 278 butyl2-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)-1H-imidazol-2-yl]ethylcarbamate

Free base. Gum.

Example 279N-{(S)-cyclohexyl[4-(4-fluorophenyl)-1-methyl-1H-imidazol-2-yl]methyl}cyclohexanamine

Hydrochloride. Melting point: 190-194° C.

Example 280 cyclohexylmethyl2-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)ethylcarbamate

Free base. Melting point: 132-134° C.

Example 2814-bromo-4′-(2-{2-[(butoxycarbonyl)amino]ethyl}-1-H-imidazol-4-yl)-1,1′-biphenyl

Free base. Melting point: 166° C.

Example 282N—((S)-cyclohexyl{4-methylthiophenyl]-1H-imidazol-2-yl}methyl)cyclohexanamine

Free base. Melting point: 96-98° C.

Example 283N-{(S)-cyclohexyl[4-(4-fluorophenyl)-1H-imidazol-2-yl]methyl}-cyclohexanamine

Free base. Melting point: 260-262° C.

Example 284N—[(S)-{4-[3,5-bis(trifluoromethyl)phenyl]-1H-imidazol-2-yl}(cyclohexyl)methyl]cyclohexanamine

Free base. Melting point: 180-182° C.

Example 285 cyclobutylmethyl2-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)ethylcarbamate

Free base. Melting point: 144-145° C.

Example 286 cyclobutylmethyl2-[4-(4-fluorophenyl)-1-H-imidazol-2-yl]ethylcarbamate

Free base. Melting point: 149-150° C.

Example 287N-{(S)-cyclohexyl[4-(3,4-difluorophenyl)-1H-imidazol-2-yl]methyl}cyclohexanamine

Free base. Melting point: 182.3° C.

Example 2884-[2-(2-{[(2-methoxyethoxy)carbonyl]amino}ethyl)-1-H-imidazol-4-yl]-1,1′-biphenyl

Free base. Melting point: 123.3° C.

Example 289(S)-1-[4-(3-bromophenyl)-1H-imidazol-2-yl]-1-cyclohexyl-N-(cyclohexylmethyl)methanamine

Free base. Melting point: 134.3° C.

Example 2904-(2-{(S)-cyclohexyl[(cyclohexylmethyl)amino]methyl}-1H-imidazol-4-yl)-N,N-diethylaniline

Hydrochloride. Melting point: 204-206° C.

Example 2912,6-ditert-butyl-4-(2-{(S)-cyclohexyl[(cyclohexylmethyl)amino]-methyl}-1H-imidazol-4-yl)phenol

Hydrochloride. Melting point: 254.6° C.

Example 2924-{2-[(S)-cyclohexyl(cyclohexylamino)methyl]-1H-imidazol-4-yl}-N,N-diethylaniline

Hydrochloride. Melting point: 204-210° C.

Example 293(S)-1-cyclohexyl-N-(cyclohexylmethyl)-1-[4-(4-fluorophenyl)-1H-imidazol-2-yl]methanamine

Free base. Melting point: 184.8° C.

Example 294 butyl2-[4-(4-tert-butylphenyl)-1H-imidazol-2-yl]ethylcarbamate

Free base. Melting point: 106-108° C.

Example 295(S)-1-cyclohexyl-N-(cyclohexylmethyl)-1-[4-(4-fluorophenyl)-1H-imidazol-2-yl]methanamine

Hydrochloride. Melting point: 190-192° C.

Example 296N—((S)-cyclohexyl{4-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}methyl)cyclohexanamine

Hydrochloride. Melting point: 214.1° C.

Example 297N—[(S)-[4-(3-bromophenyl)-1H-imidazol-2-yl](cyclohexyl)methyl]-cyclohexanamine

Hydrochloride. Melting point: 230.4° C.

Example 298N—((S)-cyclohexyl{4-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}methyl)cyclohexanamine

Free base.

Example 299 butyl 2-[4-(4-bromophenyl)-1H-imidazol-2-yl]ethylcarbamate

Free base. Melting point: 99-100° C.

Example 300 butyl2-{4-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}ethylcarbamate

Free base. Melting point: 104-105° C.

Example 301N-{(S)-cyclohexyl[4-(4-fluorophenyl)-1H-imidazol-2-yl]methyl}cycloheptanamine

Free base. Melting point: 140-142° C.

Example 302 cyclohexylmethyl2-[4-(4-tert-butylphenyl)-][H-imidazol-2-yl]ethylcarbamate

Free base. Melting point: 104-106° C.

Example 303 cyclohexylmethyl2-[4-(4′-bromo-1,1′-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate

Free base. Melting point: 130-132° C.

Example 304N—((S)-cyclohexyl{4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}methyl)cyclohexanamine

Free base. Melting point: 186-188° C.

Example 305(S)-1-cyclohexyl-N-(cyclohexylmethyl)-1-{4-[3-(trifluoromethyl)-phenyl]-1H-imidazol-2-yl}methanamine

Free base. Melting point: 143.9° C.

Example 306(S)-1-[4-(3-bromophenyl)-1H-imidazol-2-yl]-1-cyclohexyl-N-(cyclohexylmethyl)methanamine

Hydrochloride. Melting point: 206.3° C.

Example 307(S)-1-cyclohexyl-N-(cyclohexylmethyl)-1-{4-[3-(trifluoromethyl)-phenyl]-1H-imidazol-2-yl}methanamine

Hydrochloride. Melting point: 198-200° C.

Example 308(1-R)-2-cyclohexyl-1-[4-(4-fluorophenyl)-1H-imidazol-2-yl]ethanamine

Hydrochloride. Melting point: 148-149° C.

Example 309N-{(1R)-2-cyclohexyl-1-[4-(4-fluorophenyl)-1H-imidazol-2-yl]ethyl}cyclohexanamine

Free base. Melting point: 217-218° C.

Example 3104-{2-[(S)-amino(cyclohexyl)methyl]-1H-imidazol-4-yl}-N,N-diethylaniline

Hydrochloride. Melting point: 216-217° C.

Example 311(S)-1-cyclohexyl-1-[4-(3-fluorophenyl)-1H-imidazol-2-yl]methanamine

Hydrochloride. Melting point: 238-241° C.

Example 312(S)-1-cyclohexyl-N-(cyclohexylmethyl)-1-[4-(3-fluorophenyl)-1H-imidazol-2-yl]methanamine

Hydrochloride. Melting point: 180-186° C.

Example 313 butyl2-[4-(4-pyrrolidin-1-ylphenyl)-1H-imidazol-2-yl]ethylcarbamate

Free base. Melting point: 125° C.

Example 314N-{(S)-cyclohexyl[4-(3-fluorophenyl)-1H-imidazol-2-yl]methyl}cyclohexanamine

Hydrochloride. Melting point: 213.9° C.

Example 315N-{(1R)-2-cyclohexyl-1-[4-(4-fluorophenyl)-][H-imidazol-2-yl]ethyl}cyclohexanamine

Hydrochloride. Melting point: decomposes from 250° C.

Example 3164-{2-[(S)-amino(cyclohexyl)methyl]-1H-imidazol-4-yl}-2,6-ditert-butylphenol

Hydrochloride. Melting point: 222-228° C.

Example 317 butyl2-[4-(4-pyrrolidin-1-ylphenyl)-1H-imidazol-2-yl]ethylcarbamate

Hydrochloride. Melting point: 165-166° C.

Example 318(R)-1-cyclohexyl-N-(cyclohexylmethyl)-1-[4-(4-fluorophenyl)-1H-imidazol-2-yl]methanamine

Hydrochloride. Melting point: 188.2° C.

Example 3192,6-ditert-butyl-4-[4-(hydroxymethyl)-1,3-thiazol-2-yl]phenol

The compound of Example 319 can be obtained according to a protocolanalogous to that described for the compound of Example 38, Stage E ofPCT Patent Application WO 99/09829, except that ethyl bromopyruvatereplaces the 3-chloroacetoacetate in Stage 38.C and thatdisobutylaluminium hydride replaces the lithium aluminium hydride inStage 38.E.

Alternatively, this compound can also be obtained according to theprocedure described in J. Med. Chem. (1996), 39, 237-245. White solid.Melting point: 123-124° C.

Example 320meta-[4-(2,3-dihydro-1H-indol-6-yl)-1,3-thiazol-2-yl]-N-methylmethanaminehydrochloride 320.1) Mixture ofmeta-2-chloro-1-[1-(chloroacetyl)-2,3-dihydro-1H-indol-6-yl]ethanone andpara-2-chloro-1-[1-(chloroacetyl)-2,3-dihydro-1H-indol-6-yl]ethanone

1-(chloroacetyl)-2,3-dihydro-1H-indole (3.9 g; 20 mmol) is dissolved incarbon disulphide (40 ml). AlCl₃ (6.15 g; 46 mmol) is added slowly thenchloroacetyl chloride (1.835 ml; 22 mmol) is added dropwise to themixture which is then heated under reflux for 18 hours. After thereaction medium is cooled down, the CS₂ is decanted and ice-cooled watercontaining concentrated HCl is added. After extraction withdichloromethane, the organic phase is separated and dried over magnesiumsulphate before being filtered and concentrated under vacuum. Theexpected product (a 50/50 mixture of the meta and para isomers) isobtained by purification by crystallization from glacial acetic acid.White-coloured solid (1.6 g; yield of 30%).

MH+=271.

320.2) meta-2-chloro-1-(2,3-dihydro-1H-indol-6-yl)ethanone hydrochloride

Intermediate 320.1 (mixture of isomers; 1.6 g; 6.0 mmol) is dissolvedhot in a mixture of acetic acid (10 ml) and 20% HCl (2 ml). The reactionmedium is heated under reflux for 24 hours. After evaporation thenpurification by crystallization of the hydrochloride from glacial aceticacid in order to separate the mixture of isomers, the meta isomercrystallizes in the form of a brown solid (the para isomer remains inthe mother liquors) with a yield of 47%. Melting point: decompositionfrom 158° C.

MH+=196.

The meta structure of the compound was established by NMR/NOESY.

320.3)meta-[4-(2,3-dihydro-1H-indol-6-yl)-1,3-thiazol-2-yl]-N-methylmethanaminehydrochloride

The experimental protocol used is identical to that described forcompound 30.2 of Example 30, intermediate 320.2 being used as thestarting product instead of intermediate 30.1, tetrahydrofuran replacingthe toluene in the presence of one equivalent of triethylamine in orderto release the base of the salt. A brown-coloured solid is obtained witha yield of 9%. Melting point: decomposition from 235° C.

MH+=246.

Example 3212,5,7,8-tetramethyl-2-{2-[(methylamino)methyl]-1,3-thiazol-4-yl}-6-chromanolhydrochloride 321.1)6-hydroxy-N-methoxy-N,2,5,7,8-pentamethyl-2-chromanecarboxamide

2.2 g (22.0 mmol) of O,N-dimethylhydroxylamine hydrochloride,triethylamine (6.2 ml), 3.0 g (22.0 mmol) of hydroxybenzotriazole and4.2 g (22.0 mmol) of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimidehydrochloride are added successively to a solution of 5.0 g (20.0 mmol)of (R,S) 6-hydroxy-2,5,7,8-tetramethyl-2-chromanecarboxylic acid(Trolox®) in 175 ml of DMF. After the reaction mixture is stirredovernight at 25° C., the mixture is diluted with ice-cooled water andstirring is maintained for 30 more minutes. The product is extractedusing 3 times 100 ml of ethyl acetate. The organic solution is washedsuccessively with a 10% aqueous solution of sodium bicarbonate, withwater, with a 10% aqueous solution of citric acid and finally with asaturated solution of sodium chloride. The organic phase is then driedover magnesium sulphate, filtered and concentrated under vacuum. Theproduct obtained is purified by crystallization from ether in order toproduce a white-coloured solid with a yield of 63%. Melting point:139-140° C.

MH+=294.

321.2)1-(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl)ethanone

A solution of methyllithium (1.6 M; 31.25 ml; 50.0 mmol) is addeddropwise at a temperature of −30° C. to a solution of 2.93 g (10.0 mmol)of intermediate 321.1 in 100 ml of THF and the mixture is left understirring for 1 hour at −10° C. The reaction medium is hydrolyzed withNH₄Cl in a saturated aqueous solution. The product is extracted using 3times 150 ml of ethyl acetate. The organic phase is finally washed withsodium chloride in a saturated aqueous solution before being dried overmagnesium sulphate, filtered and concentrated under vacuum. The productobtained is purified by crystallization from diisopropyl ether in orderto produce a white solid with a yield of 80.7%. Melting point: 97-98° C.

MH+=248.

321.3) 2-bromo-1-(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl)ethanone

Intermediate 321.2 (0.777 g; 3.13 mmol) is dissolved in ethanol (25 ml)under a stream of argon. The solution is cooled down to 0° C. andbromine (0.18 ml; 4.20 mmol) is added in one go (see J. Am. Chem. Soc.(1999), 121, 24), then the mixture is stirred for 30 minutes allowingthe temperature to rise to ambient temperature. The excess bromine iseliminated by bubbling through argon then the mixture is left understirring for 2.5 hours. The ethanol is evaporated off and the productobtained is purified by crystallization from toluene. After filteringand washing with isopentane, a brown solid is obtained with a yield of36%. Melting point: decomposition from 125° C.

MH+=326.

321.4)2,5,7,8-tetramethyl-2-{2-[(methylamino)methyl]-1,3-thiazol-4-yl}-6-chromanolhydrochloride

The experimental protocol used is analogous to that described forcompound 30.2 of Example 30, intermediate 321.3 being used as thestarting product instead of intermediate 30.1, and benzene replacing thetoluene as solvent. The product obtained is purified by crystallizationfrom a minimum amount of dichloromethane in order to produce a whitesolid with a yield of 48%. Melting point: 153-155° C.

Example 322N-{[4-(9H-carbazol-2-yl)-1,3-thiazol-2-yl]methyl}-N-methylaminehydrochloride 322.1) 9-acetyl-9H-carbazole

This compound is obtained according to Tetrahedron (1980), 36,3017-3019. The carbazole (10 g; 60 mmol) is suspended in 150 ml ofacetic anhydride. 70% perchloric acid (0.5 ml) is added. After stirringfor 30 minutes at ambient temperature, the mixture is poured into iceand the precipitate formed is filtered. After drying under vacuum,redissolving in dichloromethane and treatment with bone charcoal, thesuspension is filtered on celite, the solvents are evaporated off andthe product recrystallized from heptane. 12 g of brown crystals (yieldof 90%) is obtained in this way. Melting point: 70-71° C. (literature:72-74° C.).

322.2) 1-(9-acetyl-9H-carbazol-2-yl)-2-chloroethanone

This compound is obtained according to a protocol analogous to that ofStage 320.1 of Example 320, using 5 g (24 mmol) of intermediate 322.1.5.4 g of the expected compound is obtained (yield of 79%). White solid.Melting point: 175-176° C.

322.3) 1-(9H-carbazol-2-yl)-2-chloroethanone

Intermediate 322.2 (2.85 g; 1 mmol) is suspended in a mixture of aceticacid (50 ml) and concentrated HCl (5 ml). The reaction medium is heatedunder reflux for 2 hours before being left to return to ambienttemperature. The new precipitate formed is filtered. After drying undervacuum, 1.9 g of a greenish solid is obtained (yield of 78%). Meltingpoint: 203-204° C.

322.4) N-{[4-(9H-carbazol-2-yl)-1,3-thiazol-2-yl]methyl}-N-methylaminehydrochloride

This compound is obtained according to a protocol analogous to that ofStage 30.2 from 487 mg (2 mmol) of intermediate 322.3 and 408 mg (2mmol) of tert-butyl 2-amino-2-thioxoethyl(methyl)carbamate. 300 mg ofthe expected product is obtained (yield of 43%). White solid. Meltingpoint: >250° C.

Example 3233,5-ditert-butyl-4′-{2-[(methylamino)methyl]-1,3-thiazol-4-yl}-1,1′-biphenyl-4-olhydrochloride 323.1)3,5′-ditert-butyl-4′-hydroxy-1,1′-biphenyl-4-carboxylic acid

5.0 g (1.41 mmol) of ethyl3′,5′-ditert-butyl-4′-hydroxy-1,1′-biphenyl-4-carboxylate (Chem. Lett.(1998), 9, 931-932) is dissolved in ethanol (25 ml). The solution iscooled down to 0° C. then a 1N solution of soda is added dropwise. Afterstirring overnight at ambient temperature, the reaction medium is heatedunder reflux in order to complete the reaction. After evaporation of thesolvents and dilution of the residue with water, the mixture obtained isacidified with a 1N solution of HCl and extraction is carried out withdichloromethane. The organic phase is washed with sodium chloride in asaturated aqueous solution before being dried over magnesium sulphate,filtered and concentrated under vacuum. The product obtained is purifiedby crystallization from diisopropyl ether in order to produce ayellow-white solid with a yield of 47%. Melting point: >240° C.

323.2)3′,5′-ditert-butyl-4′-hydroxy-N-methoxy-N-methyl-1,1′-biphenyl-4-carboxamide

The experimental protocol used is identical to that described forintermediate 321.1, with acid 323.1 replacing the Trolox® as startingproduct. A yellowish solid is obtained with a yield of 93%. Meltingpoint: 175.6-177° C.

323.3) 1-(3′,5′-ditert-butyl-4′-hydroxy-1,1′-biphenyl-4-yl)ethanone

The experimental protocol used is identical to that described forintermediate 321.2, intermediate 323.2 replacing intermediate 321.1. Awhite solid is obtained with a yield of 74%. Melting point: 144-144.7°C.

323.4)2-bromo-1-(3,5′-ditert-butyl-4′-hydroxy-1,1′-biphenyl-4-yl)ethanone

The experimental protocol used is identical to that described forintermediate 321.3, intermediate 323.3 replacing intermediate 321.2. Ayellow-orange oil is obtained which is sufficiently pure to be used inthe following stage (yield of 100%).

323.5)tert-butyl[4-(3,5′-ditert-butyl-4′-hydroxy-1,1′-biphenyl-4-yl)-1,3-thiazol-2-yl]methyl(methyl)carbamate

This compound is prepared according to the experimental protocoldescribed in Example 1, Stage 1.3, using intermediate 323.4 instead ofbromo-1-(3,5-ditert-butyl-4-hydroxyphenyl)ethanone. The expectedcompound is obtained in the form of a colourless oil with a yield of46%.

MH+=509.43.

323.6)3,5-ditert-butyl-4′-{2-[(methylamino)methyl]-1,3-thiazol-4-yl}-1,1′-biphenyl-4-olhydrochloride

0.230 g (0.452 mmol) of intermediate 323.5 is dissolved in ethyl acetate(20 ml). HCl gas is bubbled through the solution previously obtainedcooled down to 0° C. The stirred mixture is then allowed to return toambient temperature. The solid formed is filtered and washed with ethylacetate then with ether before being dried under vacuum. A white solidis obtained with a yield of 85%. Melting point: 220-221° C.

The compounds of Examples 324 to 330 are obtained according toprocedures analogous to those described for Examples 31 to 46 or abovein the part entitled “Preparation of compounds of general formula (I)”.

Example 324(1R)-1-[4-(4-fluorophenyl)-1H-imidazol-2-yl]-2-phenylethanamine

Hydrochloride. Melting point: 173-180° C.

Example 325 cyclohexylmethyl2-{4-[4-(diethylamino)phenyl]-1H-imidazol-2-yl}ethylcarbamate

Hydrochloride. Melting point: decomposes from 168° C.

Example 326 cyclohexylmethyl2-[4-(4-pyrrolidin-1-ylphenyl)-1H-imidazol-2-yl]ethylcarbamate

Free base. Melting point: 128.5° C.

Example 327N-{(1R)-1-[4-(4-fluorophenyl)-1H-imidazol-2-yl]-2-phenylethyl}cyclohexanamine

Hydrochloride. Melting point: 210-213° C.

Example 328(1R)—N-(cyclohexylmethyl)-1-[4-(4-fluorophenyl)-1H-imidazol-2-yl]-2-phenylethanamine

Hydrochloride. Melting point: from 140° C.

Example 329 cyclohexylmethyl2-[4-(3,5-ditert-butyl-4-hydroxyphenyl)-1H-imidazol-2-yl]ethylcarbamate

Hydrochloride. Melting point: 111.5° C.

Example 330 butyl2-[4-(3,5-ditert-butyl-4-hydroxyphenyl)-1H-imidazol-2-yl]ethylcarbamate

Free base. Melting point: 180.9° C.

Example 3312,6-dimethoxy-4-{2-[(methylamino)methyl]-1,3-thiazol-4-yl}phenolhydrochloride 331.1) 4-acetyl-2,6-dimethoxyphenyl acetate

3.0 g (15.3 mmol) of 3,5-dimethoxy-4-hydroxyacetophenone is dissolved indichloromethane (30 ml) and 2.53 g (18.3 mmol) of K₂CO₃ is added.Triethylamine (2.6 ml) is then added dropwise. The reaction medium iscooled down to 0° C. and acetyl chloride (1.31 ml; 18.3 mmol) is added.The mixture is stirred for 24 hours at ambient temperature then pouredinto ice-cooled water. After extraction with dichloromethane, theorganic phase is washed with sodium chloride in a saturated aqueoussolution before being dried over magnesium sulphate, filtered andconcentrated under vacuum. The product obtained is purified bycrystallization from ether in order to produce a white solid with ayield of 99%. Melting point: 145° C.

331.2) 4-(bromoacetyl)-2,6-dimethoxyphen-1 acetate

Intermediate 331.1 (0.850 g; 3.57 mmol) is solubilized in ethyl acetatethen 1.35 g (6.07 mmol) of previously dried CuBr₂ is added. The mixtureis heated under reflux for 2.5 hours before being left to return toambient temperature. Ground charcoal is added and the mixture is stirredfor 10 minutes. After filtering and evaporating to dryness, the solidobtained is taken up in diisopropyl ether. After filtering, a grey solidis obtained with a yield of 75%. Melting point: 124.2-126.3° C.

331.3)4-(2-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-1,3-thiazol-4-yl)-2,6-dimethoxyphenylacetate

Intermediate 331.3 is prepared according to an experimental protocoldescribed in Example 1, Stage 1.3, using intermediate 331.2 instead ofbromo-1-(3,5-ditert-butyl-4-hydroxyphenyl)ethanone. The expectedcompound is obtained in the form of a white solid with a yield of 55%.Melting point: 135.2-137.4° C.

331.4)tert-butyl[4-(4-hydroxy-3,5-dimethoxyphenyl)-1,3-thiazol-2-yl]methyl(methyl)carbamate

0.530 g (1.25 mmol) of intermediate 331.3 is dissolved in methanol (20ml). The solution is cooled down using an ice bath then a 1N solution ofNaOH is added dropwise. The mixture is left to return to ambienttemperature under stirring. After evaporation to dryness and dilution ofthe residue with water, the solution is neutralised using citric acidfollowed by extraction with dichloromethane. The organic phase is washedwith sodium chloride in a saturated aqueous solution before being driedover magnesium sulphate, filtered and concentrated under vacuum. Theproduct is obtained in the form of a yellow oil with a yield of 96%.

MH+=381.20.

331.5) 2,6-dimethoxy-4-{2-[(methylamino)methyl]-1,3-thiazol-4-yl}phenolhydrochloride

The experimental protocol used is identical to that described forintermediate 323.6, intermediate 331.4 replacing intermediate 323.5. Alight beige solid is obtained with a yield of 97%. Melting point:229.8-232.0° C.

Example 3322,6-diisopropyl-4-{2-[(methylamino)methyl]-1,3-thiazol-4-yl}phenolhydrochloride 332.1) 2,6-diisopropylphenyl acetate

3.45 g (16.4 mmol) of trifluoroacetic anhydride is added to 0.83 ml(14.6 mmol) of acetic acid at 0° C. while leaving the mixture to returnto ambient temperature over 2 hours. The mixture is then cooled down to0° C. and 1.95 g (11.0 mmol) of 2,6-diisopropylphenol is added dropwise.The reaction medium is maintained under stirring for 12 hours beforebeing poured into ice-cooled water. After extraction withdichloromethane, the organic phase is washed with sodium chloride in asaturated aqueous solution before being dried over magnesium sulphate,filtered and concentrated under vacuum. A colourless oil is obtainedwith a yield of 86%. This product is sufficiently pure to be useddirectly in the following stage.

332.2) 1-(4-hydroxy-3,5-diisopropylphenyl)ethanone acetate

1.94 g (14.53 mmol) of AlCl₃ is dissolved in nitrobenzene (5 ml). At thesame time, 2.0 g (9.08 mmol) of intermediate 332.1 is dissolved innitrobenzene (1 ml). The solution of intermediate 332.1 is addeddropwise to the solution of AlCl₃ at ambient temperature. The mixture istaken to 50° C. for 48 hours before being left to return to ambienttemperature. The reaction medium is then poured into ice-cooled water. A1N solution of HCl (5 ml) and then a concentrated solution of HCl (2 ml)are added. The mixture is stirred at ambient temperature followed byextraction with dichloromethane. The organic phase is washed with sodiumchloride in a saturated aqueous solution before being dried overmagnesium sulphate, filtered and concentrated under vacuum. The expectedproduct is obtained after chromatography on a silica column (eluent: 13%of ethyl acetate in heptane). After evaporation, the pure fractionsproduce a grey-white solid with a yield of 25%. Melting point: 88-93° C.

332.3) 4-acetyl-2,6-diisopropylphenyl acetate

The experimental protocol used is identical to that described forintermediate 331.1, intermediate 332.2 replacing the3,5-dimethoxy-4-hydroxyacetophenone. A sand-coloured solid is obtainedwith a yield of 95%. Melting point: 102-103° C.

332.4) 4-(bromoacetyl)-2,6-diisopropylphenyl acetate

The experimental protocol used is identical to that described forintermediate 331.2, intermediate 332.3 replacing intermediate 331.1. Ayellow oil is obtained which crystallizes slowly with a yield of 88%.This product is sufficiently pure to be used directly in the followingstage.

332.5)4-(2-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-1,3-thiazol-4-yl)-2,6-diisopropylphenylacetate

Intermediate 332.5 is prepared according to a protocol identical to thatdescribed for Example 1, Stage 1.3, using intermediate 332.4 instead ofthe bromo-1-(3,5-ditert-butyl-4-hydroxyphenyl)ethanone. The expectedcompound is obtained in the form of a pale yellow solid with a yield of76%.

MH+=447.20.

332.6)tert-butyl[4-(4-hydroxy-3,5-diisopropylphenyl)-1,3-thiazol-2-yl]methyl(methyl)carbamateacetate

The experimental protocol used is identical to that described forintermediate 331.4, intermediate 332.5 replacing intermediate 331.3. Anochre oil is obtained with a yield of 91%. This product is sufficientlypure to be used directly in the following stage.

MH+=405.20.

332.7)2,6-diisopropyl-4-[2-[(methylamino)methyl]-1,3-thiazol-4-yl}phenolhydrochloride

The experimental protocol used is identical to that described forintermediate 323.6, intermediate 332.6 replacing intermediate 323.5. Abeige-pink solid is obtained with a yield of 69%. Melting point: losesits colour at 162° C. and melts at 173-177° C.

Example 333 4-{2-[(methylamino)methyl]-1,3-thiazol-4-yl}phenolhydrochloride 333.1) 2-bromo-]-(4-hydroxyphenyl)ethanone

The experimental protocol used is identical to that described forintermediate 331.2, 4-hydroxy-acetophenone replacing intermediate 331.1.A brown-pink solid is obtained with a yield of 60%. Melting point: 118°C.

333.2)tert-butyl[4-(4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl(methyl)carbamate

Intermediate 333.2 is prepared according to a protocol identical to thatdescribed for Example 1, Stage 1.3, using intermediate 333.1 instead ofthe bromo-1-(3,5-ditert-butyl-4-hydroxyphenyl)ethanone and toluenereplacing the benzene. The expected compound is obtained in the form ofa clear-yellow oil which very slowly crystallizes cold with a yield of35%.

MH+=321.30.

333.3) 4-{2-[(methylamino)methyl]-1,3-thiazol-4-yl}phenol hydrochloride

The experimental protocol used is identical to that described forintermediate 323.6, intermediate 333.2 replacing intermediate 323.5. Apale yellow solid is obtained with a yield of 100%. Melting point:258-260° C.

Example 3342,6-ditert-butyl-4-[2-(hydroxymethyl)-1,3-thiazol-4-yl]phenol

[this is intermediate 6.d₁) of Patent Application EP 432 740]

334.1) [4-(3,5-ditert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methylpivalate

Intermediate 334.1 is prepared according to a protocol identical to thatdescribed for Example 1, Stage 1.3, using2-(tert-butylcarbonyloxy)thioacetamide instead of the2-{[(1,1-dimethylethoxy)carbonyl]methyl}amino-ethanethioamide andtoluene replacing the benzene. The expected compound is obtained in theform of a white solid with a yield of 100%. Melting point: 114.6-116.0°C.

334.2) 2,6-ditert-butyl-4-[2-(hydroxymethyl)-1,3-thiazol-4-yl]phenol

The experimental protocol used is identical to that described forintermediate 331.4, intermediate 334.1 replacing intermediate 331.3. Awhite solid is obtained with a yield of 88%. Melting point: 126.4-127.4°C.

Example 335 N-{[4-(4-aminophenyl)-1,3-thiazol-2-yl]methyl}-N-methylaminehydrochloride 335.1) 1-(4-aminophenyl)ethanone

4-amino-acetophenone (4.87 g; 36.0 mmol) is dissolved indimethylformamide (75 ml). 15 g (0.108 mol) of potassium carbonate(previously dried at 170° C. under an argon atmosphere), 7.236 g (36.0mmol) of iodobenzene, 0.4 g of copper powder and a catalytic quantity ofcopper iodide are added. The reaction mixture is taken to reflux for 12hours. After leaving the reaction medium to return to ambienttemperature, the latter is filtered on celite and poured into ice-cooledwater. After extraction with ethyl acetate, the organic phase is washedwith water before being dried over magnesium sulphate, filtered andconcentrated under vacuum. The product obtained is-purified bycrystallization from heptane in order to produce a yellow solid with ayield of 53.4%. Melting point: 105° C.

335.2) N-(4-acetylphenyl)-N-phenylacetamide

The experimental protocol used is identical to that described forintermediate 322.1, with intermediate 335.1 replacing the9-acetyl-9H-carbazole and the reaction medium being however heated for15 minutes at 70° C. After crystallization from heptane, a yellow solidis obtained with a yield of 54.2%. Melting point: 118-120° C. (value inthe literature: 122-123° C.).

335.3) N-[4-(bromoacetyl)phenyl]-N-phenylacetamide

Intermediate 335.2 (0.633 g; 2.5 mmol) is dissolved in methanol (20 ml)and 1 g (2.0 mmol) of bromination resin PVPHP (J. Macromol. Sci. Chem.(1977), A11, (3), 507-514) is added. After stirring under an argonatmosphere for 4 hours, filtration is carried out and the resins arerinsed with methanol. After evaporation of the filtrate solvents andcrystallization from methanol, a white solid is obtained with a yield of59%. Melting point: 152-153° C.

335.4)tert-butyl(4-{4-[acetyl(phenyl)amino]phenyl}-1,3-thiazol-2-yl)methyl(methyl)carbamate

Intermediate 335.4 is prepared according to a protocol identical to thatdescribed for Example 1, Stage 1.3, using intermediate 335.3 instead ofthe bromo-1-(3,5-ditert-butyl-4-hydroxyphenyl)ethanone and toluenereplacing the benzene. The expected compound is obtained in the form ofan oil with a yield of 73%.

MH+=438.30.

335.5)N-(4-{2-[(methylamino)methyl]-1,3-thiazol-4-yl}phenyl)-N-phenylacetamidehydrochloride

The experimental protocol used is identical to that described forintermediate 322.3, intermediate 335.4 replacing intermediate 322.2. Awhite-cream solid is obtained with a yield of 53%. Melting point: >250°C.

335.6) N-{[4-(4-anilinophenyl)-1,3-thiazol-2-yl]methyl}-N-methylaminehydrochloride

The experimental protocol used is identical to that described forintermediate 322.3, intermediate 335.5 replacing intermediate 322.2 andthe reaction medium being heated under reflux for 12 hours instead of 2hours. A grey solid is obtained with a yield of 68%. Meltingpoint: >250° C.

Example 3362,6-ditert-butyl-4-{2-[(dimethylamino)methyl]-1,3-thiazol-4-yl}phenolhydrochloride 336.1)4-[2-(bromomethyl)-1,3-thiazol-4-yl]-2,6-ditert-butylphenol

1.5 g (4.70 mmol) of intermediate 334.2,(2,6-ditert-butyl-4-[2-(hydroxymethyl)-1,3-thiazol-4-yl]phenol isdissolved in dichloromethane (30 ml). After adding CBr₄ (2.02 g; 6.10mmol), the reaction medium is cooled down to 0° C. PPh₃ (1.48 g; 5.63mmol) is added by fractions then the mixture is left to return toambient temperature. The reaction medium is then poured into ice-cooledwater before being extracted with dichloromethane. The organic phase iswashed with salt water before being dried over magnesium sulphate,filtered and concentrated under vacuum. The expected product is obtainedafter chromatography on a silica column (eluent: 30% of ethyl acetate inheptane), in order to produce a brown oil with a yield of 92%. Thisproduct is sufficiently pure to be used directly in the following stage.

MH+=382.20.

336.2)2,6-ditert-butyl-4-{2-[(dimethylamino)methyl]-1,3-thiazol-4-yl}phenolhydrochloride

0.8 ml (1.57 mmol) of dimethylamine and 0.4 ml (2.62 mmol) oftriethylamine are dissolved in dimethylformamide (15 ml). 0.400 g (1.05mmol) of intermediate 336.1 dissolved in dimethylformamide (5 ml) isadded then the mixture is stirred at ambient temperature for 18 hours.The reaction medium is then poured into ice-cooled water followed byextraction with ethyl acetate. The organic phase is washed with saltwater before being dried over magnesium sulphate, filtered andconcentrated under vacuum. The expected product is obtained afterchromatography on a silica column (eluent: 50% of ethyl acetate inheptane), in order to produce an orange oil with a yield of 92%. Thehydrochloride is then obtained by solubilizing the base in ether andadding 1.2 ml of a 1N solution of HCl in ether. After filtering andwashing of the solid formed with ether then with isopentane, abeige-pink solid is obtained with a yield of 15.2%. Melting point:166.8-169.0° C.

The compounds of Examples 337 to 345 are obtained according toprocedures analogous to those described for Examples 31 to 46 or abovein the part entitled “Preparation of compounds of general formula (I)”.

Example 337 cyclobutylmethyl2-[4-(4′-bromo-1,1′-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate

Hydrochloride. Melting point: 214-215° C.

Example 338 isobutyl2-[4-(4′-bromo-1,1′-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate

Free base. Melting point: 158.7° C.

Example 339 isobutyl2-[4-(4-tert-butylphenyl)-1H-imidazol-2-yl]ethylcarbamate

Free base. Melting point: 110.6° C.

Example 340 cyclobutylmethyl2-[4-(4-tert-butylphenyl)-1H-imidazol-2-yl]ethylcarbamate

Free base. Melting point: 103° C.

Example 341 cyclohexyl2-[4-(4′-bromo-1,1′-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate

Free base. Melting point: 180° C.

Example 342 cyclohexyl2-[4-(4-tert-butylphenyl)-1H-imidazol-2-yl]ethylcarbamate

Free base. Melting point: 127-130° C.

Example 343 3-[4-(4-fluorophenyl)-1H-imidazol-2-yl]propan-1-amine

Hydrochloride. Melting point: 245-246° C.

Example 344 4,4,4-trifluorobutyl2-[4-(4′-bromo-1,1′-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate

Free base. Melting point: 176.5° C.

Example 345 4,4,4-trifluorobutyl2-[4-(1,1′-biphenyl-4-yl)-1H-imidazol-2-yl]ethylcarbamate

Free base. Melting point: 157.3° C.

Example 3462,6-ditert-butyl-4-{4-[(methylamino)methyl]-1,3-thiazol-2-yl}phenolhydrochloride 346.1)4-[4-(bromomethyl)-1,3-thiazol-2-yl]-2,6-ditert-butylphenol

The experimental protocol used is identical to that described forintermediate 336.1, the compound of Example 319 replacing intermediate334.2, 1,2-dichloroethane replacing the dimethylformamide and thereaction medium being heated under reflux for 12 hours. A reddish oil isobtained with a yield of 77%. This product is used as it is directly inthe following stage.

346.2)2,6-ditert-butyl-4-{4-[(methylamino)methyl]-1,3-thiazol-2-yl}phenol

The experimental protocol used is identical to that described forintermediate 336.2, intermediate 346.1 replacing intermediate 336.1, a2N solution of methylamine in tetrahydrofuran replacing thedimethylamine and acetonitrile replacing the dimethylformamide. Thehydrochloride is obtained by solubilizing the base in ether and adding a1N solution of HCl in ether. The solid formed is filtered and purifiedby recrystallization from acetone in order to produce a white solid witha yield of 18%. Melting point: 184.0-185.0° C.

Example 3472,6-ditert-butyl-4-[2-(piperidin-1-ylmethyl)-1,3-thiazol-4-yl]phenolhydrochloride

The experimental protocol used is identical to that described forintermediate 336.2, piperidine replacing the dimethylamine. A whitesolid is obtained with a yield of 56%. Melting point: >195° C.

Example 3482,6-ditert-butyl-4-{2-[(4-methylpiperazin-1-yl)methyl]-1,3-thiazol-4-yl}phenolhydrochloride

The experimental protocol used is identical to that described forintermediate 336.2, N-methylpiperazine replacing the dimethylamine. Alight brown solid is obtained with a yield of 62%. Melting point:234.6-235.2° C.

Example 3492,6-ditert-butyl-4-[2-(piperazin-1-ylmethyl)-1,3-thiazol-4-yl]phenolhydrochloride 349.1) tert-butyl4-{[4-(3,5-ditert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}piperazine-1-carboxylate

The experimental protocol used is identical to that described forintermediate 336.2, N—Boc-piperazine replacing the dimethylamine. A paleorange solid is obtained with a yield of 64%. Melting point: 108-109° C.

349.2)2,6-ditert-butyl-4-[2-(piperazin-1-ylmethyl)-1,3-thiazol-4-yl]phenolhydrochloride

The experimental protocol used is identical to that described forintermediate 323.6, intermediate 349.1 replacing intermediate 323.5. Awhite solid is obtained with a yield of 86%. Melting point: 255.4-257.7°C.

Pharmacological Study of the Products of the Invention

Study of the Effects on the Bond of a Specific Ligand of MAO-B, [³H]Ro19-6327

The inhibitory activity of the products of the invention is determinedby measurement of their effects on the bond of a specific ligand ofMAO-B, [³H]Ro 19-6327.

a) Mitochondrial Preparation of the Cortex of Rats

The mitochondrial preparation of the cortex of rats is carried outaccording to the method described in Cesura A M, Galva M D, Imhof R andDa Prada M, J. Neurochem. 48 (1987), 170-176. The rats are decapitatedand their cortex is removed, homogenized in 9 volumes of a 0.32 Msucrose buffer, buffered to pH 7.4 with 5 mM of HEPES, then centrifugedat 800 g for 20 minutes. The supernatants are recovered and the pelletsare washed twice with the 0.32 M sucrose buffer as previously. Thecollected supernatants are centrifuged at 10000 g for 20 minutes. Thepellets obtained are suspended in a Tris buffer (50 mM Tris, 130 mMNaCl, 5 mM KCl, 0.5 mM EGTA, 1 mM MgCl₂, pH 7.4) and centrifuged at10000 g for 20 minutes. This stage is repeated twice, and the finalpellet, corresponding to the mitochondrial fraction, is stored at −80°C. in the Tris buffer. The proteinic content of the preparation isdetermined by the Lowry method.

b) Bond of [³H]Ro 19-6327

100 μl of the mitochondrial preparation (2 mg protein/ml) are incubatedfor 1 hour at 37° C. in an Eppendorf tube, in the presence of 100 μl of[³H] Ro 19-6327 (33 nM, final concentration) and 100 μl of Tris buffercontaining or not containing the inhibitors. The reaction is stopped bythe addition of 1 ml of unlabelled Tris buffer into each tube, then thesamples are centrifuged for 2 minutes at 12000 g. The supernatants areremoved by suction and the pellets washed with 1 ml of Tris buffer. Thepellets are then solubilized in 200 μl of sodium dodecyl sulphate (20%weight/volume) for 2 hours at 70° C. The radioactivity is determined bycounting the samples using liquid scintillation.

c) Results

The compounds of Examples 1, 3, 6, 22, 24, 26 to 29, 323 and 332described above show an IC₅₀ lower than 10 μM.

Study of the Effects on Lipidic Peroxidation of the Cerebral Cortex ofthe Rat

The inhibitory activity of the products of the invention is determinedby measuring their effects on the degree of lipidic peroxidation,determined by the concentration of malondialdehyde (MDA). The MDAproduced by peroxidation of unsaturated fatty acids is a good indicationof lipidic peroxidation (H Esterbauer and K H Cheeseman, Meth. Enzymol.(1990) 186: 407-421). Male Sprague Dawley rats weighing 200 to 250 g(Charles River) were sacrificed by decapitation. The cerebral cortex isremoved, then homogenized using a Thomas potter in a 20 mM Tris-HClbuffer, pH=7.4. The homogenate is centrifuged twice at 50000 g for 10minutes at 4° C. The pellet is stored at −80° C. On the day of theexperiment, the pellet is resuspended at a concentration of 1 g/15 mland centrifuged at 515 g for 10 minutes at 4° C. The supernatant is usedimmediately to determine the lipidic peroxidation. The homogenate ofrat's cerebral cortex (500 μl) is incubated at 37° C. for 15 minutes inthe presence of the compounds to be tested or of the solvent (10 μl).The lipidic peroxidation reaction is initiated by adding 50 μl of FeCl₂at 1 mM, EDTA at 1 mM and ascorbic acid at 4 mM. After incubation for 30minutes at 37° C., the reaction is stopped by adding 50 μl of a solutionof hydroxylated di-tert-butyl toluene (BHT, 0.2%). The MDA is quantifiedusing a colorimetric test, by reacting a chromogenic reagent (R),N-methyl-2-phenylindol (650 μl) with 200 oil of the homogenate for 1hour at 45° C. The condensation of an MDA molecule with two molecules ofreagent R produces a stable chromophore the maximum absorbencewavelength of which is equal to 586 nm. (Caldwell et al. European J.Pharmacol. (1995) 285, 203-206). The compounds of Examples 1 to 3, 6 to17, 20 to 30, 320, 321, 323, 331 and 332 described above show an IC₅₀lower than 10 μM.

Bond Test on the Cerebral Sodium Channels of the Cortex of the Rat

The test consists in measuring the interaction of the compoundsvis-à-vis the bond of tritiated batrachotoxin on the voltage-dependentsodium channels according to the protocol described by Brown (J.Neurosci. (1986), 6, 2064-2070).

Preparation of Homogenates of Cerebral Cortices of the Rat

The cerebral cortices of Sprague-Dawley rats weighing 230-250 g (CharlesRiver, France) are removed, weighed and homogenized using a Potterhomogenizer provided with a teflon piston (10 strokes) in 10 volumes ofisolation buffer the composition of which is as follows (sucrose 0.32 M;KHPO₄ 5 mM; pH 7.4). The homogenate is subjected to a firstcentrifugation at 1000 g for 10 minutes. The supernatant is removed andcentrifuged at 20000 g for 15 minutes. The pellet is taken up in theisolation buffer and centrifuged at 20000 g for 15 minutes. The pelletobtained is resuspended in incubation buffer (HEPES 50 mM; KCl 5.4 mM;MgSO₄ 0.8 mM; glucose 5.5 mM; choline chloride 130 mM pH 7.4) thenaliquoted and stored at −80° C. until the day of assay. The finalprotein concentration is comprised between 4 and 8 mg/ml. The assay ofproteins is carried out using a kit marketed by BioRad (France).

Measurement of the Bond of Tritiated Batrachotoxin

The bond reaction is carried out by incubating for 1 hour 30 minutes at25° C. 100 μl of homogenate of rat cortex containing 75 μg of proteinswith 100 μl of [³H] batrachotoxin-A 20-alpha benzoate (37.5 Ci/mmol,NEN) at 5 nM (final concentration), 200 μl of tetrodotoxin at 1 μM(final concentration) and scorpion venom at 40 μg/ml (finalconcentration) and 100 μl of incubation buffer alone or in the presenceof the products to tested at different concentrations. The non-specificbond is determined in the presence of 300 μM of veratridine and thevalue of this non-specific bond is subtracted from all the other values.The samples are then filtered using a Brandel (Gaithersburg, Md., USA)using Unifilter GF/C plates pre-incubated with 0.1% of polyethyleneimine (20 μl/well) and rinsed twice with 2 ml of filtration buffer(HEPES 5 mM; CaCl₂ 1.8 mM; MgSO₄ 0.8 mM; choline chloride 130 mM; BSA0.01%; pH 7.4). After having added 20 μl of Microscint 0®, theradioactivity is counted using a liquid scintillation counter (Topcount,Packard). The measurement is carried out in duplicate. The results areexpressed as a % of the specific bond of tritiated batrachotoxinrelative to the control.

Results

The compounds of Examples 1, 6, 7, 11, 13, 15, 17, 20, 24, 31 to 38, 42,43, 46 to 48, 53, 56, 57, 59 to 61, 64 to 80, 82 to 88, 92 to 95, 97,105, 106, 108, 110, 113, 117, 118, 121 to 123, 125, 128, 130 to 139, 142to 145, 149, 151, 152, 154, 162 to 166, 168 to 178, 181, 183 to 186,188, 190 to 196, 198 to 206, 208 to 210, 212 to 218, 220 to 231, 233 to250, 252 to 259, 261 to 281, 283 to 288, 293 to 313, 324 and 338 to 340described above all show an IC₅₀ lower than or equal to 1 μM. Moreover,the compounds of Examples 3, 9, 10, 26, 28 to 30 and 321 described aboveshow an IC₅₀ lower than or equal to 3.5 μM.

1-21. (canceled)
 22. A method of treating Parkinson's disease inwarm-blooded animals comprising administering to warm-blooded animals inneed thereof an amount of a compound of the formula

in racemic, enantiomeric form or any combination of these forms, inwhich A is

in which Q is selected from the group consisting of H, —OR²², —NR²³R²⁴,phenyl optionally substituted by at least one substituent independentlyselected from the group consisting of —OH, cyano, nitro, alkyl, alkoxyor —NR¹⁰R¹¹ and a group with two substituents representing together amethylenedioxy or ethylenedioxy, or Q is selected from the groupconsisting of —COPh, —SO₂Ph or —CH₂Ph, said COPh, —SO₂Ph or —CH₂Phoptionally substituted on its aromatic parts by at least oneindependently alkyl or alkoxy or halogen, R¹⁰ and R¹¹ are independentlyselected from the group consisting of hydrogen, alkyl and —COR¹², or R¹⁰and R¹¹ form together with the nitrogen atom an optionally substitutedheterocycle containing 4 to 7 members and 1 to 3 heteroatoms includingthe nitrogen atom already present, the additional heteroatoms beingindependently selected from the group consisting of O, N and S, R¹² isselected from the group consisting of hydrogen, alkyl, alkoxy andNR¹³R¹⁴, R¹³ and R¹⁴ are independently; hydrogen or alkyl, or R¹³ andR¹⁴ form together with the nitrogen atom an optionally substitutedheterocycle containing 4 to 7 members and 1 to 3 heteroatoms includingthe nitrogen atom already present, the additional heteroatoms beingchosen independently from the group consisting of O, N and S, R²² isselected from the group consisting of hydrogen, alkyl and aryloptionally substituted by at least one substituent selected from thegroup consisting of alkyl, OH, halogen, nitro and alkoxy, R²³ and R²⁴are independently selected from the group consisting of hydrogen, alkyland —CO—R²⁵, R²⁵ is alkyl, and R¹⁹, R²⁰ and R²¹ are independentlyselected from the group consisting of hydrogen, halogen, —OH, —SR²⁶,alkyl, cycloalkyl, alkenyl, alkoxy, cyano, nitro, —SO₂NHR⁴⁹, —CONHR⁵⁵,—S(O)_(q)R⁵⁶, —NH(CO)R⁵⁷, —CF₃, —OCF₃ and NR²⁷R²⁸, R²⁷ and R²⁸ areindependently selected from the group consisting of hydrogen, alkyl and—COR²⁹, or R²⁷ and R²⁸ form together with the nitrogen atom anoptionally substituted heterocycle containing 4 to 7 members and 1 to 3heteroatoms including the nitrogen atom already present, the additionalheteroatoms being independently selected from the group consisting of O,N and S, R⁴⁹ and R⁵⁵ are independently each time that they occur,hydrogen or alkyl or alkylcarbonyl, q is an integer from 0 to 2, R⁵⁶ andR⁵⁷ are, each time that they occur, hydrogen or alkyl or alkoxy, R²⁹ isselected from the group consisting of hydrogen, alkyl, alkoxy and—NR³⁰R³¹, R³⁰ and R³¹ are independently selected from the groupconsisting of hydrogen and alkyl, or R³⁰ and R³¹ form together with thenitrogen atom an optionally substituted heterocycle containing 4 to 7members and 1 to 3 heteroatoms including the nitrogen atom alreadypresent, the additional heteroatoms being independently selected fromthe group consisting of O, N and S, Y is O or S; R¹ is hydrogen, alkyl,aminoalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, trifluoromethyl,alkyl, alkenyl, allenyl, allenylalkyl, alkynyl, cyanoalkyl,—(CH₂)_(g)-Z¹R³⁹, —(CH₂)_(g)—COR⁴⁰, —(CH₂)_(g)—NHCOR⁷, aryl, aralkyl,arylcarbonyl, heteroarylalkyl and aralkylcarbonyl, the aryl group of thearyl, aralkyl, arylcarbonyl, heteroarylalkyl or aralkylcarbonyl itselfbeing optionally substituted by at least one substituent selected fromthe group consisting of alkyl, halogen, alkoxy, nitro, cyano,cyanoalkyl, amino, alkylamino, dialkylamino, —(CH₂)_(k)-Z²R³⁹ and—(CH₂)_(k)—COR⁴⁰⁻, Z¹ and Z² are selected from the group consisting of abond, —O—, —NR⁴¹— and —S—, R³⁹ and R⁴¹ are independently each time thatthey occur, selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl and cyanoalkyl, R⁴⁰ is, independently each time that itoccurs, selected from the group consisting of hydrogen, alkyl, allenyl,allenylalkyl, alkenyl, alkynyl, cyanoalkyl, alkoxy and NR⁴²R⁴³, R⁴² andR⁴³ are independently, each time that they occur, selected from thegroup consisting of hydrogen, alkyl, allenyl, allenylalkyl, alkenyl,alkynyl and cyanoalkyl and R² is selected from the group consisting ofhydrogen, alkyl, aminoalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,trifluoromethylalkyl, —(CH₂)_(g)—NHCOR⁷¹, aralkyl and heteroarylalkyloptionally substituted on the aryl or heteroaryl by at least one memberselected from the group consisting of halogen, alkyl, alkoxy, hydroxyl,cyano, nitro, amino, alkylamino and dialkylamino, R⁷⁰ and R⁷¹ areindependently alkyl or alkoxy; or R¹ and R², taken together with thecarbon atom which carries them, form a carbocycle with 3 to 7 members; Bis selected from the group consisting of hydrogen, alkyl,—(CH₂)_(g)-Z³R⁴⁴ and carbocyclic aryl optionally substituted 1 to 3times by a member selected from the group consisting of halogen, alkyland alkoxy of 1 to 6 carbon atoms, hydroxy, cyano, nitro, amino,alkylamino, dialkylamino and a carbocyclic aryl, Z³ is selected from thegroup consisting of a bond, —O—, NR⁴⁵— and —S—, R⁴⁴ and R⁴⁵ areindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, allenyl, allenylalkyl and cyanoalkyl; Ω is NR⁴⁶R⁴⁷ orOR⁴⁸; R⁴⁶ and R⁴⁷ are independently selected from the group consistingof hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl,allenyl, allenylalkyl, cyanoalkyl, —(CH₂)_(g)-Z⁴R⁵⁰, —(CH₂)_(k)—COR⁵¹,—(CH₂)_(k)—COOR⁵¹, —(CH₂)_(k)—CONHR⁵¹, —SO₂R⁵¹, aryl, aralkyl,aryloxyalkyl, arylcarbonyl, arylimino, aralkylcarbonyl, heteroaryl,pyridinylalkyl or pyridinylcarbonyl, the aryl or heteroaryl of saidaryl, aralkyl, aryloxyalkyl, arylcarbonyl, arylimino, aralkylcarbonyl,heteroaryl, pyridinylalkyl or pyridinylcarbonyl being optionallysubstituted by at least one member independently selected from the groupconsisting of halogen, alkyl, alkoxy, hydroxy, nitro, cyano, cyanoalkyl,amino, alkylamino, dialkylamino, -Z⁵R⁵⁰, —(CH₂)_(k)—COR⁵¹ and—(CH₂)_(k)—COOR⁵¹, Z⁴ and Z⁵ are selected from the group consisting of abond, —O—, —NR⁵²— and —S—, or R⁴⁶ and R⁴⁷ taken together form with thenitrogen atom a non-aromatic heterocycle with 4 to 8 ring members, theelements of the chain being selected from the group consisting of—CH(R⁵³)—, —NR⁵⁴—, —O—, —S— and —CO—, R⁵⁰ and R⁵² are independently eachtime that they occur, selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, allenyl, allenylalkyl and cyanoalkyl, R⁵¹ is,independently each time that they occur, selected from the groupconsisting of hydrogen, cycloalkyl and cycloalkylalkyl in which thecycloalkyl has 3 to 7 carbon atoms, alkyl of 1 to 8 carbon atoms,alkenyl, alkynyl, allenyl, allenylalkyl, cyanoalkyl, alkoxyalkyl,NR⁵⁸R⁵⁹, aryl or aralkyl, said aryl or aralkyl optionally substituted byat least one member selected from the group consisting of halogen, alkyland alkoxy, R⁵⁸ and R⁵⁹ are independently a member selected from thegroup consisting of hydrogen, alkyl, alkenyl, alkynyl, allenyl,allenylalkyl and cyanoalkyl, R⁵³ and R⁵⁴ are independently a memberselected from the group consisting of hydrogen or —(CH₂)_(k)-Z⁷R⁶⁰ and—(CH₂)_(k)—COR⁶¹, Z⁷ is a member selected from the group consisting of abond, —O—, —NR⁶²— and —S—, R⁶⁰ and R⁶² are independently a memberselected from the group consisting of hydrogen, alkyl, alkenyl, allenyl,allenylalkyl, alkynyl, cyanoalkyl, aryl, aralkyl, arylcarbonyl,aralkylcarbonyl, pyridinyl, pyridinylalkyl or pyridinylcarbonyl, thearyl or pyridinyl of the aryl, aralkyl, arylcarbonyl, aralkylcarbonyl,pyridinyl, pyridinylalkyl or pyridinylcarbonyl being optionallysubstituted by at least one substituent selected from the groupconsisting of alkyl, halogen, nitro, alkoxy, cyano, cyanoalkyl,—(CH₂)_(k)-Z⁸R⁶³ and —(CH₂)_(k)—COR⁶⁴, R⁶¹ is a member selected from thegroup consisting of hydrogen, alkyl, allenyl, allenylalkyl, alkenyl,alkynyl, cyanoalkyl, alkoxy and NR⁶⁵R⁶⁶, R⁶⁵ and R66 are independentlyselected from the group consisting of hydrogen, alkyl, allenyl,allenylalkyl, alkenyl, alkynyl and cyanoalkyl, Z⁸ is a member selectedfrom the group consisting of a bond, —O—, —NR⁶⁷— and —S—, R⁶³ and R⁶⁷are independently a member selected from the group consisting ofhydrogen, alkyl, allenyl, allenylalkyl, alkenyl, alkynyl and cyanoalkyl,R⁶⁴ is a member of the group consisting of hydrogen, alkyl,allenylalkyl, alkenyl, alkynyl, cyanoalkyl, alkoxy and NR⁶⁸R⁶⁹, R⁶⁸ andR⁶⁹ are independently a member selected from the group consisting ofhydrogen, alkyl, allenyl, allenylalkyl, alkenyl, alkynyl cyanoalkyl, andR⁴⁸ is a member selected from the group consisting of hydrogen, alkyl,alkynyl and cyanoalkyl; g and p, each time that they occur, beingindependently integers from 1 to 6, and k and n, each time that theyoccur, being independently integers from 0 to 6; or a salt thereofsufficient to treat Parkinson's disease.
 23. The method of claim 22wherein A is

in which Q is selected from the group consisting of —H, —OR²², —SR²²,—NR²³R²⁴, phenyl optionally substituted by at least one member selectedfrom the group consisting of halogen, —OH, cyano, nitro, alkyl, alkoxyand —NR¹⁰R¹¹ and a group of two substituents together beingmethylenedioxy or ethylenedioxy, or Q is selected from the groupconsisting of —COPh, —OPh, —SPh, —SO₂Ph or —CH₂Ph, said —COPh, —OPh,—SPh, —SO₂Ph or —CH₂Ph being optionally substituted on its aromatic partby at least one member selected from the group consisting of alkyl,alkoxy and halogen, R¹⁰ and R¹¹ are independently selected from thegroup consisting of hydrogen, alkyl, or R¹⁰ and R¹¹ form together withthe nitrogen atom an optionally substituted heterocycle containing 4 to7 ring members and 1 to 3 heteroatoms including the nitrogen atomalready present, the additional heteroatoms being independently selectedfrom the group consisting of O, N and S, R²² is selected from the groupconsisting of hydrogen, alkyl and aryl optionally substituted by atleast one member selected from the group consisting of alkyl, —OH,halogen, nitro and alkoxy, R²³ and R²⁴ are, independently, hydrogen, oralkyl or —CO—R²⁵, R²⁵ is alkyl, and R¹⁹, R²⁰ and R²¹ are independentlyselected from the group consisting of hydrogen, halogen, OH, SR²⁶,alkyl, cycloalkyl, alkenyl, alkoxy, cyano, nitro, —SO₂NHR⁴⁹, —CONHR⁵⁵,—S(O)_(q)R⁵⁶, —NH(CO)R⁵⁷, —CF₃, —OCF₃ and NR²⁷R²⁸, R²⁶ is hydrogen oralkyl, R²⁷ and R²⁸ are independently selected from the group consistingof hydrogen, alkyl and —COR²⁹, or R²⁷ and R²⁸ form together with thenitrogen atom an optionally substituted heterocycle containing 4 to 7ring members and 1 to 3 heteroatoms including the nitrogen atom alreadypresent, the additional heteroatoms being selected from the groupconsisting of O, N and S, R⁴⁹ and R⁵⁵ are, independently each time thatthey occur, hydrogen or alkyl or alkylcarbonyl, q is an integer from 0to 2, R⁵⁶ and R⁵⁷ are, independently each time that they occur, hydrogenor alkyl or alkoxy, R²⁹ is selected from the group consisting ofhydrogen, alkyl, alkoxy and —NR³⁰R³¹, R³⁰ and R³¹ are independentlyselected from the group consisting of hydrogen, alkyl, or R³⁰ and R³¹form together with the nitrogen atom an optionally substitutedheterocycle containing 4 to 7 ring members and 1 to 3 heteroatomsincluding the nitrogen atom already present, the additional heteroatomsbeing selected from the group consisting of O, N and S.
 24. The methodof claim 22 wherein A is

in which Q is —OR²², —SR²², —NR²³R²⁴, phenyl optionally substituted byat least one member selected from the group consisting of halogen, —OH,cyano, nitro, alkyl, alkoxy and —NR¹⁰R¹¹, R¹⁰ and R¹¹ are independentlyselected from the group consisting of hydrogen or alkyl, or R¹⁰ and R¹¹form together with the nitrogen atom an optionally substitutedheterocycle containing 4 to 7 ring members and 1 to 3 heteroatomsincluding the nitrogen atom already present, the additional heteroatomsbeing selected from the group consisting of O, N and S, R²² is selectedfrom the group consisting of hydrogen, alkyl and aryl optionallysubstituted by at least one member selected from the group consisting ofalkyl, —OH, halogen, nitro and alkoxy, R²³ and R²⁴ are, independently,hydrogen or alkyl, and R¹⁹, R²⁰ and R²¹ are independently selected fromthe group consisting of hydrogen, halogen, —OH, —SR²⁶, alkyl, alkenyl,alkoxy and NR²⁷R²⁸, R²⁶ is hydrogen or alkyl, R²⁷ and R²⁸ areindependently selected from the group consisting of hydrogen, alkyl, orR²⁷ and R²⁸ form together with the nitrogen atom an optionallysubstituted heterocycle containing 4 to 7 members and 1 to 3 heteroatomsincluding the nitrogen atom already present, the additional heteroatomsbeing selected from the group consisting of O, N and S.
 25. The methodof claim 24 wherein A is

in which Q is selected from the group consisting of —OR²², —SR²² andphenyl substituted by —OH and optionally by at least one member selectedfrom the group consisting of halogen, —OH, alkyl and alkoxy, R²² ishydrogen or alkyl, and R¹⁹, R²⁰ and R²¹ are independently selected fromthe group consisting of hydrogen, halogen, —OH, SR²⁶, alkyl and alkoxy,R²⁶ is hydrogen or alkyl.
 26. The method of claim 25 wherein thecompound corresponds to formula (I)₃ in which Y is O A is

in which Q is —OH, two of the R¹⁹, R²⁰ and R²¹ are selected from thegroup consisting of alkyl, alkoxy, alkylthio, amino, alkylamino anddialkylamino and the third is selected from the group consisting ofhydrogen, alkyl, alkoxy, alkylthio, amino, alkylamino and dialkylamino,or Q is phenyl substituted by —OH and at least one member selected fromthe group consisting of halogen, —OH, alkyl, alkoxy and —NR¹⁰R¹¹, R¹⁰and R¹¹ are independently hydrogen or alkyl.
 27. The method of claim 26wherein A is

in which Q is —OH, two of the R¹⁹, R²⁰ and R²¹ are alkyl and the thirdis H, or Q is phenyl substituted by-OH and at least one alkyl.
 28. Themethod of claim 22 wherein Y is O; A is

in which Q is —OH, two of the R¹⁹, R²⁰ and R²¹ are alkyl and the thirdis hydrogen, or in which Q is phenyl substituted by —OH and at least onealkyl; B is hydrogen; n is 0 or 1; R¹ and R² both are hydrogen. and Ω isNR⁴⁶R⁴⁷, R⁴⁶ is selected from the group consisting of hydrogen, alkyl,alkynyl, hydroxyalkyl and cyanoalkyl and R⁴⁷ is hydrogen or alkyl or R⁴⁶and R⁴⁷ form together with the nitrogen atom which carries them anon-aromatic heterocycle with 5 to 7 ring members, the additionalmembers are —CH₂— or —NH—.
 29. The method of claim 28, wherein thecompound is selected from the group consisting of4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-2-thiazolemethanamine;2-[({4-[3,5-di(tert-butyl)-4-hydroxyphenyl]-1,3-thiazol-2-yl}methyl)(methyl)amino]-acetonitrile;2,6-di(tert-butyl)-4-(2-{[(2-hydroxyethyl)(methyl)amino]methyl}-1,3-thiazol-4-yl)phenol;4-[{[4-(3,5-ditert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}(methyl)amino]-butanenitrile;2,6-ditert-butyl-4-(4-(2-[methyl(2-propynyl)amino]ethyl-1,3-oxazol-2-yl)phenol;3-[(2-[2-(3,5-ditert-butyl-4-hydroxyphenyl)-1,3-oxazol-4-yl]ethyl)(methyl)amino]-propanenitrile;2,6-ditert-butyl-4-{4-[2-(1-piperazinyl)ethyl]-1,3-oxazol-2-yl}phenol;and the pharmaceutically acceptable salts of the latter.
 30. The methodof claim 22 wherein the compound is selected from the group consistingof 2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4-oxazoleethanol,2,6-ditert-butyl-4-(4-{2-[methyl(2-propynyl)amino]ethyl}-1,3-oxazol-2-yl)phenol,[{2-[2-(3,5-ditert-butyl-4-hydroxyphenyl)-1,3-oxazol-4-yl]ethyl}(methyl)amino]acetonitrile,3-[{2-[2-(3,5-ditert-butyl-4-hydroxyphenyl)-1,3-oxazol-4-yl]ethyl}(methyl)amino]-propanenitrile,2,6-ditert-butyl-4-{4-[2-(1-piperazinyl)ethyl]-1,3-oxazol-2-yl}phenolhydrochloride,2,6-ditert-butyl-4-[4-(hydroxymethyl)-1,3-thiazol-2-yl]phenol and2,6-ditert-butyl-4-{4-[(methylamino)methyl]-1,3-thiazol-2-yl}phenolhydrochloride.